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ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-C12-sphingomyelin/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-C12-sphingomyelin/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-glucosylceramide/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-glucosylceramide/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-lactosylceramide/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-lactosylceramide/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylcholine (16:0, 6:0)/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylcholine (16:0, 6:0)/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylethanolamine (16:0, 6:0)/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylethanolamine (16:0, 6:0)/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species. Translocation of (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylethanolamine is inhibited by the presence of the putative physiological substrate lipid A
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylethanolamine (18:1)/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylethanolamine (18:1)/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species. Translocation of (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylethanolamine is inhibited by the presence of the putative physiological substrate lipid A
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylglycerol (16:0, 6:0)/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylglycerol (16:0, 6:0)/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylserine (16:0, 6:0)/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylserine (16:0, 6:0)/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species
-
-
?
ATP + H2O + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylserine (18:1)/in
ADP + phosphate + (7-nitrobenz-2-oxa-1,3-diazole)-phosphatidylserine (18:1)/out
-
bacterial membrane vesicles isolated from Escherichia coli overexpressing MsbA display ATP-dependent translocation of several fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labelled phospholipid species
-
-
?
ATP + H2O + daunorubicin[side 1]
ADP + phosphate + daunorubicin[side 2]
-
-
-
?
ATP + H2O + DMSO/in
ADP + phosphate + DMSO/out
-
-
-
-
?
ATP + H2O + ethidium/in
ADP + phosphate + ethidium/out
ATP + H2O + Hoechst 33342
ADP + phosphate + Hoechst 33342/out
-
-
-
-
?
ATP + H2O + Hoechst 33342/in
ADP + phosphate + Hoechst 33342/out
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
ATP + H2O + Lipid A/in
ADP + phosphate + Lipid A/out
ATP + H2O + lipo-oligosaccharide/in
ADP + phosphate + lipo-oligosaccharide/out
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
ATP + H2O + phosphoethanolamine[side 1]
ADP + phosphate + phosphoethanolamine[side 2]
fluorescently NBD (7-nitrobenz-2-oxa-1,3-diazole)-labeled
-
-
?
ATP + H2O + verapamil/in
ADP + phosphate + verapamil/out
-
-
-
-
?
additional information
?
-
ATP + H2O + ethidium/in
ADP + phosphate + ethidium/out
-
-
-
-
?
ATP + H2O + ethidium/in
ADP + phosphate + ethidium/out
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + Lipid A/in
ADP + phosphate + Lipid A/out
-
-
-
-
?
ATP + H2O + Lipid A/in
ADP + phosphate + Lipid A/out
-
substrate binding structure, overview
-
-
?
ATP + H2O + Lipid A/in
ADP + phosphate + Lipid A/out
-
MsbA contains two substrate-binding sites that communicate with both the nucleotide-binding domain and with each other, one is a high affinity binding site for the physiological substrate, lipid A, and the other site interacts with drugs with comparable affinity, overview
-
-
?
ATP + H2O + lipo-oligosaccharide/in
ADP + phosphate + lipo-oligosaccharide/out
-
-
-
?
ATP + H2O + lipo-oligosaccharide/in
ADP + phosphate + lipo-oligosaccharide/out
MsbA protein shown as a member of the ABC transporter family, differences to MsbA protein of Escherichia coli determined
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
MsbA is an essential ABC transporter involved in lipid A transport across the cytoplasmic membrane
-
-
?
additional information
?
-
-
MsbA functions as an ATP-dependent lipid translocase that transports lipid A from the inner to the outer leaflet of the cytoplasmic membrane. MsbA is able to hydrolyze TNP-ATP, albeit at a lower rate than its corresponding ATPase activity
-
-
?
additional information
?
-
-
MsbA is an essential ABC transporter in Gram-negative bacteria
-
-
?
additional information
?
-
concerted conformational rearrangements occur during MsbA ATPase cycle
-
-
?
additional information
?
-
MsbA cannot efficiently transport a substrate lacking phosphorylation at the 4'-position of lipid A
-
-
?
additional information
?
-
purified MsbA from Escherichia coli displays high ATPase activity, and binds to lipids and lipid-like molecules, including lipid A, with affinity in the low micromolar range. Purified MsbA is reconstituted into proteoliposomes of Escherichia coli lipid and shows ability to translocate 7-nitrobenz-2-oxa-1,3-diazole (NBD)-labeled lipid derivatives. In this system, the protein displays maximal lipid flippase activity of 7.7 nmol of lipid translocated per mg of protein over a 20 min period for an acyl chain-labeled phosphatidylethanolamine derivative. Lipid flippase activity requires ATP hydrolysis, and is dependent on the concentration of ATP and NBD-lipid. MsbA can accommodate lipids with bulky carbohydrate headgroups
-
-
?
additional information
?
-
-
purified MsbA from Escherichia coli displays high ATPase activity, and binds to lipids and lipid-like molecules, including lipid A, with affinity in the low micromolar range. Purified MsbA is reconstituted into proteoliposomes of Escherichia coli lipid and shows ability to translocate 7-nitrobenz-2-oxa-1,3-diazole (NBD)-labeled lipid derivatives. In this system, the protein displays maximal lipid flippase activity of 7.7 nmol of lipid translocated per mg of protein over a 20 min period for an acyl chain-labeled phosphatidylethanolamine derivative. Lipid flippase activity requires ATP hydrolysis, and is dependent on the concentration of ATP and NBD-lipid. MsbA can accommodate lipids with bulky carbohydrate headgroups
-
-
?
additional information
?
-
MsbA is an essential ABC transporter in Gram-negative bacteria
-
-
?
additional information
?
-
-
binding of of amphipathic drugs, e.g. of daunorubicin, quercetin, verapamil, or propafenone GP12, alters the protein conformation
-
-
?
additional information
?
-
MsbA cannot efficiently transport a substrate lacking phosphorylation at the 4'-position of lipid A
-
-
?
additional information
?
-
simultaneous high affinity binding to MsbA of lipid A (the putative physiological substrate) and daunorubicin, which suggests that the protein has separate binding sites for these two compounds. The effects of nucleotide and lipid A/daunorubicin binding to MsbA are additive, and binding could occur in any order. The two substrate-binding sites appear to communicate with each other, and also with the nucleotide-binding site in the nucleotide-binding domains, NBDs. The two monomers function independently, and do not interact co-operatively with each other, analysis using MIANS-labeled enzyme, MIANS, i.e. 2-(4-maleimidylanilino)naphthalene-6-sulfonic acid, is a cysteine-reactive fluorescent probe for soluble and membrane-bound proteins, fluorescence quenching studies. The percentage quenching values observed for lipid A and daunorubicin are also similar regardless of the order of titration. The binding affinity for lipid A is reduced about 5fold at 23°C and about 7fold at 10°C when the daunorubicin-binding site is occupied first
-
-
?
additional information
?
-
-
the MsbA2 protein in the inner membrane is essential to ensure the symbiotic interaction with the host plant alfalfa. Sinorhizobium meliloti invades plant cells via plant-derived structures known as infection threads. However, MsbA2 is not essential for the membrane transport of either lipopolysaccharide or phospholipids in the organism, but in the absence of MsbA2 the polysaccharide content of Sinorhizobium meliloti is altered
-
-
?
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ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
ATP + H2O + Lipid A/in
ADP + phosphate + Lipid A/out
ATP + H2O + lipo-oligosaccharide/in
ADP + phosphate + lipo-oligosaccharide/out
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
additional information
?
-
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + lipid A-core oligosaccharide[side 1]
ADP + phosphate + lipid A-core oligosaccharide[side 2]
-
-
-
?
ATP + H2O + Lipid A/in
ADP + phosphate + Lipid A/out
-
-
-
-
?
ATP + H2O + Lipid A/in
ADP + phosphate + Lipid A/out
-
MsbA contains two substrate-binding sites that communicate with both the nucleotide-binding domain and with each other, one is a high affinity binding site for the physiological substrate, lipid A, and the other site interacts with drugs with comparable affinity, overview
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
-
-
?
ATP + H2O + lipopolysaccharide/in
ADP + phosphate + lipopolysaccharide/out
-
MsbA is an essential ABC transporter involved in lipid A transport across the cytoplasmic membrane
-
-
?
additional information
?
-
-
MsbA functions as an ATP-dependent lipid translocase that transports lipid A from the inner to the outer leaflet of the cytoplasmic membrane. MsbA is able to hydrolyze TNP-ATP, albeit at a lower rate than its corresponding ATPase activity
-
-
?
additional information
?
-
-
MsbA is an essential ABC transporter in Gram-negative bacteria
-
-
?
additional information
?
-
MsbA is an essential ABC transporter in Gram-negative bacteria
-
-
?
additional information
?
-
-
the MsbA2 protein in the inner membrane is essential to ensure the symbiotic interaction with the host plant alfalfa. Sinorhizobium meliloti invades plant cells via plant-derived structures known as infection threads. However, MsbA2 is not essential for the membrane transport of either lipopolysaccharide or phospholipids in the organism, but in the absence of MsbA2 the polysaccharide content of Sinorhizobium meliloti is altered
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
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(2E)-3-[1-cyclopropyl-7-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]naphthalen-2-yl]prop-2-enoic acid
(2E)-3-[6-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]quinolin-3-yl]prop-2-enoic acid
(2E)-3-[6-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]quinolin-3-yl]prop-2-enoic acid
(2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid
D-20133
-
lipid-based drug, high affinity binding to MsbA
ethidium
-
antimitotic drug, vinblastine, directly competes with ethidium for binding to MsbA
Hoechst 33342
-
complete inhibition of MsbA-mediated Hoechst33342 transport by 0.025 mM taxol, noncompetitive kinetics with Ki of 0.0066 mM, overview
ilmofosine
-
lipid-based drug, high affinity binding to MsbA
lipid A
translocation of NBD-phosphatidylethanolamine is inhibited by the presence of the putative physiological substrate lipid A, probably due to competition for flipping of 7-nitrobenz-2-oxa-1,3-diazole-labeled phosphoethanolamine (NBD-PE)
lipopolysaccharide
-
dependent on the origin
(2E)-3-[1-cyclopropyl-7-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]naphthalen-2-yl]prop-2-enoic acid
-
(2E)-3-[1-cyclopropyl-7-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]naphthalen-2-yl]prop-2-enoic acid
-
(2E)-3-[6-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]quinolin-3-yl]prop-2-enoic acid
-
(2E)-3-[6-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]quinolin-3-yl]prop-2-enoic acid
-
(2E)-3-[6-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]quinolin-3-yl]prop-2-enoic acid
a quinoline compound with potent activity on purified Escherichia coli MsbA
(2E)-3-[6-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]quinolin-3-yl]prop-2-enoic acid
-
(2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid
selective small-molecule antagonist with bactericidal activity and a dual-mode inhibitory mechanism. (2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. (2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid gains access to MsbA through the bulk membrane. The 2-chloro-6 cyclopropylphenyl substituent of (2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid (A-ring) exhibits strong electron density and makes van der Waals interactions with side chains from transmembrane domains TM4 (L171, A175 and V178), TM5 (A259 and L263) and TM6 (M291 and L294). The quinoline core of (2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid (B-ring) is orthogonal to the plane of the phenyl substituent, where it is partially enclosed by residues from transmembrane domains TM4 (V178, S179 and I182), TM5 (A259) and TM6 (M295 and L298). A259 and M295 side chains contact the 4-cyclopropyl substitution of the quinoline core and delineate the inhibitor binding-pocket from the inner vestibule of MsbA. (2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid stabilizes a catalytically incompetent state of the transporter. The inhibitor may have broad relevance across the ABC transporter superfamily
(2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid
i.e. G907, selective small-molecule antagonist with bactericidal activity and a dual-mode inhibitory mechanism. G907-MsbA binding structure, overview. In the outward-facing StMsbA structure, the G907 pocket is markedly deformed and expected to perturb inhibitor binding. This substantial perturbation of the binding site during the transport cycle defines G907 as an inward-facing state-dependent inhibitor. The inhibitor may have broad relevance across the ABC transporter superfamily
vanadate
-
-
vanadate
inhibitory effect of vanadate on the ATPase activity of MsbA
vinblastine
-
antimitotic drug, vinblastine, directly competes with ethidium for binding to MsbA
additional information
-
no inhibition by substrate lipid A also at high concentration, poor inhibition by verapamil, colchicine, and daunorubicine, poor inhibition by lipid-based drugs D-20133, and D-21266, along with LY335979
-
additional information
analysis of ABC transporter inhibition mechanism, small molecule inhibitor library screening, overview. (2E)-3-[6-[1-(2-chloro-6-cyclopropylphenyl)ethoxy]-4-cyclopropylquinolin-3-yl]prop-2-enoic acid traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains
-
additional information
analysis of ABC transporter inhibition mechanism, small molecule inhibitor library screening, overview
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
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0.0064
lipid A
-
pH 7.5, 37°C, recombinant His-tagged enzyme
0.048 - 0.05
lipopolysaccharide
-
pH 7.5, 37°C, recombinant His-tagged enzyme
additional information
additional information
-
0.002
ATP
-
pH 7.0, 37°C, mutant H537A
0.005
ATP
-
pH 7.0, 37°C, mutant S423C/E506Q
0.005
ATP
-
pH 7.0, 37°C, mutant S423C/H537A
0.012
ATP
-
pH 7.0, 37°C, mutant E506Q
0.117
ATP
-
pH 7.0, 37°C, wild-type
0.161
ATP
-
pH 7.0, 37°C, mutant S423C
0.379
ATP
reconstituted purified recombinant His-tagged enzyme in liposomes prepared from Escherichia coli phospholipids, pH 7.5, 37°C, ATP hydrolysis in presence of 10 mM Mg2+ and 0.021 mM Kdo2-lipid A
0.41
ATP
-
pH 7.5, 37°C, unlabeled recombinant MsbA
0.495
ATP
8 mM ATP, chimeric protein, reconstitution form
0.52
ATP
-
pH 7.5, 37°C, MIANS-labeled recombinant MsbA
0.52
ATP
recombinant His-tagged wild-type enzyme, ATPase activity, pH 7.5, 37°C
0.573
ATP
8 mM ATP, detergent solubilized form of protein
0.573
ATP
pH 7.5, 37°C, detergent-solubilized recombinant His6-tagged enzyme, 8 mM ATP, ATPase activity
0.878
ATP
reconstituted purified recombinant His-tagged enzyme in liposomes prepared from Escherichia coli phospholipids, pH 7.5, 37°C, ATP hydrolysis in presence of 10 mM Mg2+
1.31
ATP
in 50 mM HEPES (pH 7.5), 10 mM MgCl2, at 37°C
2
ATP
-
pH 7.5, 37°C, recombinant His-tagged enzyme
3.6
ATP
8 mM ATP, chimeric protein, detergent solubilized form
4.5
ATP
8 mM ATP, reconstitution form of protein
4.5
ATP
pH 7.5, 37°C, reconstituted recombinant His6-tagged enzyme, 8 mM ATP, ATPase activity
additional information
additional information
-
ligand binding kinetics
-
additional information
additional information
-
lipid binding kinetics, overview
-
additional information
additional information
kinetics of the conformational change from ATP-bound T561C to the dynamic equilibrium during continuous ATP hydrolysis (in MgATP) by stopped flow measurements, kinetics of the conformational changes of mutant enzymes
-
additional information
additional information
Michaelis-Menten kinetics of MsbA ATPase activity
-
additional information
additional information
-
Michaelis-Menten kinetics of MsbA ATPase activity
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evolution
enzyme MsbA encoded is a member of the ABC transporter family
evolution
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
evolution
the msbA gene product belongs to the superfamily of ABC transporters, the ATP-binding cassette (ABC)-transporter superfamily, a universally conserved family of proteins characterized by a highly conserved ATP-binding domain
evolution
the MsbA protein is an essential ABC (ATP-binding-cassette) superfamily member in Gram-negative bacteria
evolution
-
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
-
evolution
-
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
-
evolution
-
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
-
evolution
-
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
-
evolution
-
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
-
evolution
-
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
-
evolution
-
Pseudomonas aeruginosa MsbA encoded is a member of the ABC transporter family, but this protein has distinctive features when compared with other MsbA proteins
-
malfunction
accumulation of lipid A species in the inner membranes of htrB- cells when msbA and orfE are not expressed. The tetra-acylated lipid A precursors that accumulate in htrB mutants may not be transported as efficiently by MsbA as are penta- or hexaacylated lipid A species. LPS accumulates in the inner membranes of htrB-deficient mutants. Introduction of msbA and orfE on low copy plasmids partially restores translocation of LPS to the outer membrane at 42°C in htrB mutants. The Escherichia coli msbA gene also functions as a multicopy suppressor of htrB mutations
malfunction
depletion or loss of function of MsbA results in the accumulation of lipopolysaccharide and phospholipids in the inner membrane of Escherichia coli
malfunction
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
malfunction
-
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
malfunction
-
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
malfunction
-
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
malfunction
-
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
malfunction
-
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
malfunction
-
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
malfunction
-
depletion or loss of function of MsbA results in the accumulation of lipopolysaccharide and phospholipids in the inner membrane of Escherichia coli
-
malfunction
-
accumulation of lipid A species in the inner membranes of htrB- cells when msbA and orfE are not expressed. The tetra-acylated lipid A precursors that accumulate in htrB mutants may not be transported as efficiently by MsbA as are penta- or hexaacylated lipid A species. LPS accumulates in the inner membranes of htrB-deficient mutants. Introduction of msbA and orfE on low copy plasmids partially restores translocation of LPS to the outer membrane at 42°C in htrB mutants. The Escherichia coli msbA gene also functions as a multicopy suppressor of htrB mutations
-
malfunction
-
msbA is an essential gene in this organism and mutation in this gene is lethal to the bacterium. Disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans. Gene msbA from Escherichia coli (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
metabolism
the enzyme is involved in the biosynthetic pathways of lipid A
metabolism
the enzyme is involved in the biosynthetic pathways of lipid A
metabolism
the enzyme is involved in the lipid A biosynthesis. MsbA cannot efficiently transport a substrate lacking phosphorylation at the 4'-position of lipid A. This last essential step of lipid A biosynthesis is catalysed by LpxK, the two proteins are concatenated in some bacteria, suggesting tight coupling of their cellular activities
metabolism
-
the enzyme is involved in the biosynthetic pathways of lipid A
-
metabolism
-
the enzyme is involved in the biosynthetic pathways of lipid A
-
metabolism
-
the enzyme is involved in the biosynthetic pathways of lipid A
-
metabolism
-
the enzyme is involved in the biosynthetic pathways of lipid A
-
metabolism
-
the enzyme is involved in the biosynthetic pathways of lipid A
-
metabolism
-
the enzyme is involved in the biosynthetic pathways of lipid A
-
metabolism
-
the enzyme is involved in the biosynthetic pathways of lipid A
-
physiological function
-
the enzyme regulates starvation responses, adhesion and affects cellulase secretion in response to environmental cues. The enzyme modulates both the cell wall integrity and filamentous growth MAPK pathways influencing adhesion, biofilm formation and secretion and contributes to filamentous growth and stress resistance when exposed to nutrient-poor conditions
physiological function
ATP-binding cassette (ABC) multidrug exporters are embedded in the plasma membrane and actively extrude cytotoxic drugs from the cell. Alternating access models for ABC exporters including the multidrug and lipid A transporter MsbA from Escherichia coli suggest a role for nucleotide as the fundamental source of free energy. These models involve cycling between conformations with inward and outward facing substrate-binding sites in response to engagement and hydrolysis of ATP at the nucleotide-binding domains. MsbA also utilizes another major energy currency in the cell by coupling substrate transport to a transmembrane electrochemical proton gradient. The dependence of ATP-dependent transport on proton coupling, and the stimulation of MsbA-ATPase by the chemical proton gradient highlight the functional integration of both forms of metabolic energy. MsbA catalyzes proton-coupled substrate transport in proteoliposomes. Energy coupling by MsbA, detailed overview
physiological function
Escherichia coli MsbA is a lipid-activated ATPase with a proposed role in phospholipid export
physiological function
genes msbA and orfE, forming an operon, are essential for bacterial viability under all growth conditions tested. Gene msbA is a multicopy suppressor of gene htrB, overview. When cloned in vectors maintained at two to four copies per cell, the msbA gene complements most of the HtrB phenotypes, including the morphological alterations, the overproduction of phospholipids, and the lethality exhibited at non-permissive temperatures. Neither HtrB nor MsbB can fully substitute for MsbA function
physiological function
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
physiological function
MsbA is an essential ABC family transporter in lipid A and phospholipid biosynthesis, ATP-dependent transport of nascent core-lipid A molecules across the inner membrane by MsbA. The Escherichia coli msbA gene also functions as a multicopy suppressor of htrB mutations (temperature-sensitive growth of an Escherichia coli mutant lacking htrB and its suppression by extra copies of msbA). The HtrB-catalyzed transfer of laurate to lipid A may be necessary for efficient core-lipid A transport and MsbA and/or OrfE are components of the transport machinery
physiological function
the enzme is an LPS transporters. LPS transporters are ABC exporters that are known to export extremely hydrophobic compounds, such as lipids, drugs, and steroids. MsbA facilitates flipping of the lipid A-core structure across the inner membrane and exports antibiotics and chemotherapeutic drugs
physiological function
the enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa, but gene msbA from Escherichia coli cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
physiological function
the homodimeric ATP-dependent lipid translocase or flippase transports lipid A from the inner to the outer leaflet of the cytoplasmic membrane
physiological function
the movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA, structure of LPS in complex with EcMsbA, overview
physiological function
the movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA, structure of LPS in complex with StMsbA, overview
physiological function
the movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. The ABC transporter MsbA flips the lipid to the outer leaflet of the inner membrane and the O-antigen is attached by WaaL to create LPS. LPS and the periplasmic protein, LptA (EC 2.7.8.43), are two essential components of Gram-negative bacteria. LPS (endotoxin) is asymmetrically distributed in the outer leaflet of the outer membrane of Gram-negative bacteria such as Escherichia coli and plays a role in the organism's natural defense in adverse environmental conditions. LptA is a member of the lipopolysaccharide transport protein (Lpt) family, which also includes LptC, LptDE, and LptBFG2, that functions to transport LPS through the periplasm to the outer leaflet of the outer membrane after MsbA flips LPS across the inner membrane
physiological function
the msbA gene expressed from a low-copy-number plasmid vector is able to suppress the temperature-sensitive growth phenotype of an Escherichia coli htrB null mutant as well as the accumulation of phospholipids. The msbA gene is essential for bacterial viability at all temperatures. Role for MsbA as a translocator of lipopolysaccharides or its precursors
physiological function
-
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
-
physiological function
-
ATP-binding cassette (ABC) multidrug exporters are embedded in the plasma membrane and actively extrude cytotoxic drugs from the cell. Alternating access models for ABC exporters including the multidrug and lipid A transporter MsbA from Escherichia coli suggest a role for nucleotide as the fundamental source of free energy. These models involve cycling between conformations with inward and outward facing substrate-binding sites in response to engagement and hydrolysis of ATP at the nucleotide-binding domains. MsbA also utilizes another major energy currency in the cell by coupling substrate transport to a transmembrane electrochemical proton gradient. The dependence of ATP-dependent transport on proton coupling, and the stimulation of MsbA-ATPase by the chemical proton gradient highlight the functional integration of both forms of metabolic energy. MsbA catalyzes proton-coupled substrate transport in proteoliposomes. Energy coupling by MsbA, detailed overview
-
physiological function
-
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
-
physiological function
-
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
-
physiological function
-
the enzyme regulates starvation responses, adhesion and affects cellulase secretion in response to environmental cues. The enzyme modulates both the cell wall integrity and filamentous growth MAPK pathways influencing adhesion, biofilm formation and secretion and contributes to filamentous growth and stress resistance when exposed to nutrient-poor conditions
-
physiological function
-
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
-
physiological function
-
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
-
physiological function
-
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
-
physiological function
-
Escherichia coli MsbA is a lipid-activated ATPase with a proposed role in phospholipid export
-
physiological function
-
MsbA is an essential ABC family transporter in lipid A and phospholipid biosynthesis, ATP-dependent transport of nascent core-lipid A molecules across the inner membrane by MsbA. The Escherichia coli msbA gene also functions as a multicopy suppressor of htrB mutations (temperature-sensitive growth of an Escherichia coli mutant lacking htrB and its suppression by extra copies of msbA). The HtrB-catalyzed transfer of laurate to lipid A may be necessary for efficient core-lipid A transport and MsbA and/or OrfE are components of the transport machinery
-
physiological function
-
lipopolysaccharide of Pseudomonas aeruginosa is a major constituent of the outer membrane, and it is composed of three distinct regions: lipid A, core oligosaccharide, and O antigen. Lipid A and core oligosaccharides (OS) are synthesized and assembled at the cytoplasmic side of the inner membrane and then translocated to the periplasmic side of the membrane where lipid A-core becomes the acceptor of the O antigens. The translocation through the inner membrane is catalyzed by ABC transporter MsbA. The enzyme is involved in the transport of lipid A-core, and not just lipid A, from the cytoplasmic side of the inner membrane to the periplasmic side. Gene msbA is essential in the organism. Expression of Escherichia coli MsbA but not Pseudomonas aeruginosa MsbA confers resistance to erythromycin in Pseudomonas aeruginosa. Neither MsbA nor MsbAEc have an impact on the susceptibility of Pseudomonas aeruginosa to ciprofloxacin, tobramycin, or ofloxacin used in treatment of Pseudomonas aeruginosa infections
-
additional information
inward facing structure of EcMsbA in complex with LPS, structure comparisons and molecular basis of active lipid transport, overview
additional information
nucleotide-free MsbA has an open structure where the two NBDs are separated by 50 A. The transmembrane (TM) helices are arranged in two wings that form a V-shaped chamber open to the cytoplasm and the inner leaflet of the bilayer. In the AMPPNP structure, the closed structure, the two NBDs form the canonical ATP dimer while the two TM wings of the transporter pack in the cytoplasm and split in an outward-facing conformation at the extracellular side. To create this opening, a twisting motion repacks the TM helices changing the identity of the swapped helices between the two monomers. Whereas TM1-TM2 share intersubunit contacts with TM3-TM6 in the closed structure, TM4-TM5 join the other subunit in the open conformation. As a result the inward and outward openings are mediated by different sets of helices. Nucleotide-free MsbA also crystallizes in an alternative conformation (closed-apo) that has the two NBDs closer than the open-apo and the chamber partially occluded. But it has the same helix packing in the TMD as the open-apo structure. Purified MsbA reconstitutes in liposomes. Structure-function analysis, detailed overview
additional information
outward facing structure of Salmonella typhimurium MsbA (StMsbA) in complex with LPS, structure comparisons and molecular basis of active lipid transport, overview
additional information
preparation of proteoliposomes from Escherichia coli phospholipids demonstrating the equal incorporation of purified transport-inactive triple mutant MsbA-DED, truncated mutant MsbA-MD, mutant MsbA-DELTAK382 and wild-type MsbA, and the absence of membrane proteins in empty control liposomes. Proton-coupled substrate transport in proteoliposomes. The enhanced efficiency of efflux by full-length MsbA compared with the nucleotide-binding domain (NBD)-less protein is also found in the ability of the MsbA proteins to confer cellular resistance to the antibiotic erythromycin. The ATP-dependent dimerization of the NBDs with closure of the substrate-binding cavity towards the inside surface of the membrane facilitates capture of substrate from the cellular interior and/or inner membrane leaflet, and enables efflux against a larger drug concentration gradient and/or lipid-water partition coefficient. The ATP dependence therefore enhances the directionality of the transport reaction
additional information
reconstitution of purified MsbA into proteoliposomes, method, overview
additional information
-
reconstitution of purified MsbA into proteoliposomes, method, overview
additional information
structure comparisons and molecular basis of active lipid transport, overview
additional information
structure of the AMPPNP-bound MsbA, structure-activity model, overview
additional information
-
preparation of proteoliposomes from Escherichia coli phospholipids demonstrating the equal incorporation of purified transport-inactive triple mutant MsbA-DED, truncated mutant MsbA-MD, mutant MsbA-DELTAK382 and wild-type MsbA, and the absence of membrane proteins in empty control liposomes. Proton-coupled substrate transport in proteoliposomes. The enhanced efficiency of efflux by full-length MsbA compared with the nucleotide-binding domain (NBD)-less protein is also found in the ability of the MsbA proteins to confer cellular resistance to the antibiotic erythromycin. The ATP-dependent dimerization of the NBDs with closure of the substrate-binding cavity towards the inside surface of the membrane facilitates capture of substrate from the cellular interior and/or inner membrane leaflet, and enables efflux against a larger drug concentration gradient and/or lipid-water partition coefficient. The ATP dependence therefore enhances the directionality of the transport reaction
-
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A281C
the mutant displays a reduction in ATP-dependent Hoechst 33342 export activity
D510G
random mutagenesis, the mutant cannot support Escherichia coli growth, but it retains the ability to bind ATP in vitro
D512G
random mutagenesis, the mutant is able to hydrolyze ATP 3fold faster than the wild-type enzyme
E208A
the mutant shows greatly reduced activity compared to the wild type enzyme
E208A/A281C
the mutant displays a strong reduction in ATP-dependent Hoechst 33342 export activity
E208A/K212A
the mutant shows greatly reduced activity compared to the wild type enzyme
E208Q
the mutant shows 44.4% of wild type activity
E506Q
-
mutation leads to dysfunctional protein, loss of cell viability. Mutant protein maintains its ability to bind ATP, but hydrolysis is severely inhibited. Hydrolysis does occur over time. Protein adopts a closed dimer conformation, indicating that events within the cell can induce a stable, closed conformation of the MsbA homodimer that does not reopen even in the absence of nucleotide
H537A
-
mutation leads to dysfunctional protein, loss of cell viability. Mutant protein maintains its ability to bind ATP, but hydrolysis is severely inhibited. Hydrolysis does occur over time. Protein adopts a closed dimer conformation, indicating that events within the cell can induce a stable, closed conformation of the MsbA homodimer that does not reopen even in the absence of nucleotide
I385C
site-directed mutagenesis of the spin-labeled reporter site
I385C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes slight changes upon MgATP/Vi binding
I385C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
I517V
random mutagenesis, the MsbA mutant protein is still partly functional due to the fact that an Ile to Val change is a fairly conservative substitution, or because in the MDR proteins a Val residue is present at this position
K212A
the mutant shows greatly reduced activity compared to the wild type enzyme
L504C
site-directed mutagenesis of the spin-labeled reporter site
L504C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding, the mutant exhibits a general broadening of the spectrum
L504C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
L509P
random mutagenesis, the mutant cannot support Escherichia coli growth, but it retains the ability to bind ATP in vitro
L511P
random mutagenesis, the mutant is able to bind ATP at near-wild-type levels but is unable to maintain cell viability in an in vivo growth assay, it is dysfunctional at some point after ATP binding. The L511P mutation prevents effective ATP hydrolysis, only small amounts of ATP are hydrolyzed
Q485C
site-directed mutagenesis of the spin-labeled reporter site
Q485C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
Q485C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
S289A/S290A
-
site-directed mutagenesis, the mutant enzyme is not stimulated by taxol in contrast to the wild-type enzyme. The mutation does not alter the interaction of MsbA with Hoechst33342 but reduces the level of inhibition of MsbA-mediated Hoechst33342 transport by taxol. The mutant MsbA is affected in the binding and transport of ethidium
S380C
site-directed mutagenesis of the spin-labeled reporter site
S380C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding and exhibits an additional shift (approximately 30%) toward the immobilized population
S380C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
S423C/E506Q
-
significantly diminished rates of hydrolysis, about 4% of wild-type
S423C/H537A
-
significantly diminished rates of hydrolysis, about 4% of wild-type
S423C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes slight changes upon MgATP/Vi binding
S423C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
S482C
site-directed mutagenesis of the spin-labeled reporter site
S482C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
S482C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
T541C
site-directed mutagenesis of the spin-labeled reporter site
T541C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
T541C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
V426C
site-directed mutagenesis of the spin-labeled reporter site
V426C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
V426C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding, the mutant shows a more immobile spectrum in the presence of MgATP
V534C
site-directed mutagenesis of the spin-labeled reporter site
V534C/D512G
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes slight changes upon MgATP/Vi binding
V534C/L511P
site-directed mutagenesis, the additional mutation of the spin-labeled reporter site causes changes upon MgATP/Vi binding
D512G
-
random mutagenesis, the mutant is able to hydrolyze ATP 3fold faster than the wild-type enzyme
-
L511P
-
random mutagenesis, the mutant is able to bind ATP at near-wild-type levels but is unable to maintain cell viability in an in vivo growth assay, it is dysfunctional at some point after ATP binding. The L511P mutation prevents effective ATP hydrolysis, only small amounts of ATP are hydrolyzed
-
S423C
-
site-directed mutagenesis of the spin-labeled reporter site
-
C88A/C315A/E506Q/T561C
site-directed mutagenesis, replacement of the catalytic carboxylate E506, the catalytically deficient mutant E506Q/T561C has a very low activity (1% of the T561C activity)
C88A/C315A/T561C
site-directed mutagenesis, inactive cysteine mutant, the ATPase activity of T561C is highly dependent on temperature, addition of Mg2x01 decreased the LRET signal intensity of the ATP-bound T561C, and subsequent addition of Vi increased the signal back toward the ATP-bound state
C88S/C315S
site-directed mutagenesis
A270T
site-directed mutagenesis, temperature-sensitive MsbA allele, the mutation renders cells temperature-sensitive for growth and lipid export, the mutant displays ATPase activity similar to that of the wild-type protein at 30°C but is significantly reduced at 42°C
A270T
site-directed mutagenesis, the mutation causes the protein to become inactive at high temperatures
S423C
-
mutant shows a Vmax similar to WT
S423C
site-directed mutagenesis of the spin-labeled reporter site
A270T
-
site-directed mutagenesis, the mutation causes the protein to become inactive at high temperatures
-
A270T
-
site-directed mutagenesis, temperature-sensitive MsbA allele, the mutation renders cells temperature-sensitive for growth and lipid export, the mutant displays ATPase activity similar to that of the wild-type protein at 30°C but is significantly reduced at 42°C
-
D41N/E149Q/D252N
site-directed mutagenesis, triple mutant MsbA-DED, comprising mutations D41N in transmembrane helix (TMH) 1, E149Q in TMH 3 and D252N in TMH 5, is transport inactive
D41N/E149Q/D252N
-
site-directed mutagenesis, triple mutant MsbA-DED, comprising mutations D41N in transmembrane helix (TMH) 1, E149Q in TMH 3 and D252N in TMH 5, is transport inactive
-
C315S
-
site-idrected mutagenesis, structure analysis in comparison to the wild-type enzyme
C315S
site-directed mutagenesis of the active site Cys
C315S
site-directed mutagenesis, the mutant ATPase activity of the C88S and C315S mutants does not differ substantially from that of wild-type MsbA
C88S
-
site-directed mutagenesis, structure analysis in comparison to the wild-type enzyme
C88S
site-directed mutagenesis of the active site Cys
C88S
site-directed mutagenesis, the mutant ATPase activity of the C88S and C315S mutants does not differ substantially from that of wild-type MsbA
additional information
-
construction of point and deletion muitants, e.g. DELTAK382, change-in-specificity mutations colocalize in a major groove in each of the two wings of transmembrane helices, that point away from one another to ward the periplasm. Near the apex of the groove, the periplasmic side of transmembrane helice 6, TMH6, in both monomers contains a hot spot of change-in-specificity mutations and residues which, when replaced with cysteines in ABCB1, covalently interact with thiol-reactive drug analogues, drug-protein interaction analysis, overview
additional information
mutant phenotypes, overview
additional information
amorphadiene, the precursor of antimalarial drug artemisinin from Artemisia annua, is secreted from Escherichia coli cells overexpressing the biosynthetic pathway. The overexpression of transporters in the lipopolysaccharide transport system (msbA, lptD, lptCABFG) improves amorphadiene (AD) production. AD production in both early stage (8 h) and final stage (24 h) is increased by more than twofold in the strains that overexpress lptCABFG or msbA. But co-overexpression of LptCABFG and LptD or LptD and TolC does not enhance AD-specific production synergistically, despite the fact that the AD titer is increased mainly due to the increased cell density, overview
additional information
generation of an Escherichia coli msbA insertion knockout mutant. The mutation has a deleterious effect on bacterial growth or viability. The insertion mutation affects the expression of both genes, msbA and orfE, overview
additional information
overexpression of msbA suppresses mutations in the htrB lipid A acyltransferase, as MsbA can transport the tetra-acylated LPS produced in htrB mutants, albeit inefficiently
additional information
random PCR mutagenesis of gene msbA resulting in six independent mutants, four of which result in single-amino-acid substitutions in non-conserved residues, the temperature-sensitive mutants are able to support cell growth at 30°C but not at 43°C. The remaining two mutants behave as recessive lethals, the mutations result in single-amino-acid substitutions in Walker motif B, one of the two highly conserved regions of the ATP-binding domain. The latter two mutants cannot support Escherichia coli growth, but they both retain the ability to bind ATP in vitro. N-acetyl [3H]-glucosamine, a precursor of Iipopolysaccharides, accumulates at the non-permissive temperature in the inner membrane of either htrB null or msbA conditional lethal strains. Translocation of the precursor to the outer membrane is restored by transformation with a plasmid containing the wild-type msbA gene. The Ts- phenotype exhibited at 43°C can be suppressed by supplementing the medium with 10 mM Mg2+ or Ca2+
additional information
-
random PCR mutagenesis of gene msbA resulting in six independent mutants, four of which result in single-amino-acid substitutions in non-conserved residues, the temperature-sensitive mutants are able to support cell growth at 30°C but not at 43°C. The remaining two mutants behave as recessive lethals, the mutations result in single-amino-acid substitutions in Walker motif B, one of the two highly conserved regions of the ATP-binding domain. The latter two mutants cannot support Escherichia coli growth, but they both retain the ability to bind ATP in vitro. N-acetyl [3H]-glucosamine, a precursor of Iipopolysaccharides, accumulates at the non-permissive temperature in the inner membrane of either htrB null or msbA conditional lethal strains. Translocation of the precursor to the outer membrane is restored by transformation with a plasmid containing the wild-type msbA gene. The Ts- phenotype exhibited at 43°C can be suppressed by supplementing the medium with 10 mM Mg2+ or Ca2+
additional information
-
mutant phenotypes, overview
-
additional information
construction of a truncated mutant form MsbA-MD of wild-type MsbA that lacks the nucleotide-binding domain (NBD). Truncated mutant MsbA-DELTAK382 exhibits a strongly reduced ATPase activity due to the absence of the catalytic Walker A lysine residue. Preparation of proteoliposomes from Escherichia coli phospholipids demonstrating the equal incorporation of purified transport-inactive triple mutant MsbA-DED, truncated mutant MsbA-MD, mutant MsbA-DELTAK382 and wild-type MsbA, and the absence of membrane proteins in empty control liposomes. Observations on active drug transport by MsbA-MD and wild-type MsbA show that wild-type MsbA is more efficient than MsbA-MD in vivo
additional information
-
construction of a truncated mutant form MsbA-MD of wild-type MsbA that lacks the nucleotide-binding domain (NBD). Truncated mutant MsbA-DELTAK382 exhibits a strongly reduced ATPase activity due to the absence of the catalytic Walker A lysine residue. Preparation of proteoliposomes from Escherichia coli phospholipids demonstrating the equal incorporation of purified transport-inactive triple mutant MsbA-DED, truncated mutant MsbA-MD, mutant MsbA-DELTAK382 and wild-type MsbA, and the absence of membrane proteins in empty control liposomes. Observations on active drug transport by MsbA-MD and wild-type MsbA show that wild-type MsbA is more efficient than MsbA-MD in vivo
-
additional information
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
additional information
-
disruption of the chromosomal msbA is achieved only when a functional copy of the gene is provided in trans, mutation in the gene is lethal to the bacterium. Gene msbA from Escherichia coli K-12 (msbAEc) cannot cross complement the msbA merodiploid cells of Pseuomonas aeruginosa
-
additional information
change-in-speci?city mutations colocalize in a major groove in each of the two wings of transmembrane helices, that point away from one another to ward the periplasm. Near the apex of the groove,the periplasmic side of transmembrane helice 6, TMH6, in both monomers contains a hot spot of change-in-speci?city mutations and residues which, when replaced with cysteines in ABCB1, covalently interact with thiol-reactive drug analogues
additional information
the mutant enzymes are T561C and E506Q/T561C are labeled with MIANS fluorescent probes
additional information
the mutant enzymes are T561C and E506Q/T561C are labeled with thiol-reactive LRET probes, time course of nucleotide-binding domains (NBDs) association/dissociation monitored by LRET, kinetics of the conformational changes
additional information
-
disruption of the msbA2 gene with pJH104 creates a transcriptional fusion to the uidA gene, encoding GUS. The m1021 msbA2::pJH104t insertion mutant induces a plant defence response in alfalfa, and shows altered polysaccharide content but does not affect the transport of phosphate-containing lipids, phenotype, overview
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The reconstituted Escherichia coli MsbA protein displays lipid flippase activity
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Escherichia coli (P60752), Escherichia coli
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