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Literature summary for 3.6.5.2 extracted from

  • Hwang, J.; Tseitin, V.; Ramnarayan, K.; Shenderovich, M.D.; Inouye, M.
    Structure-based design and screening of inhibitors for an essential bacterial GTPase, Der (2012), J. Antibiot., 65, 237-243.
    View publication on PubMed
Search for more literature for 3.6.5.2

Application

Application Comment Organism
drug development the enzyme Der may be an ideal cellular target against which antibiotics can be developed, lead compounds inhibiting Der GTPase provide scaffolds for the development of antibiotics against antibiotic-resistant pathogenic bacteria Staphylococcus aureus
drug development the enzyme Der may be an ideal cellular target against which antibiotics can be developed, lead compounds inhibiting Der GTPase provide scaffolds for the development of antibiotics against antibiotic-resistant pathogenic bacteria Thermotoga maritima
drug development the enzyme Der may be an ideal cellular target against which antibiotics can be developed, lead compounds inhibiting Der GTPase provide scaffolds for the development of antibiotics against antibiotic-resistant pathogenic bacteria Escherichia coli
drug development the enzyme Der may be an ideal cellular target against which antibiotics can be developed, lead compounds inhibiting Der GTPase provide scaffolds for the development of antibiotics against antibiotic-resistant pathogenic bacteria Deinococcus radiodurans

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of the enzyme in Escherichia coli Escherichia coli
recombinant expression of the enzyme in Escherichia coli strain BL21(DE3) Thermotoga maritima
recombinant expression of the His-tagged enzyme in Escherichia coli strain BL21(DE3) Staphylococcus aureus
recombinant expression of the His-tagged enzyme in Escherichia coli strain BL21(DE3) Deinococcus radiodurans

Crystallization (Commentary)

Crystallization (Comment) Organism
crystal structure analysis, PDB ID 1MKY, computer-aided pharmacophore modeling and modeling of GTP and GDP binding to the enzyme, overview Thermotoga maritima
Thermotoga maritima crystal structure analysis, PDB ID 1MKY, computer-aided pharmacophore modeling and modeling of GTP and GDP binding to the enzyme, overview Escherichia coli

Inhibitors

Inhibitors Comment Organism Structure
3-([(2E)-2-cyano-3-(4-methoxy-3-[(naphthalen-1-ylcarbonyl)oxy]phenyl)prop-2-enoyl]amino)benzoic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Deinococcus radiodurans
3-([(2E)-2-cyano-3-(4-methoxy-3-[(naphthalen-1-ylcarbonyl)oxy]phenyl)prop-2-enoyl]amino)benzoic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Escherichia coli
3-([(2E)-2-cyano-3-(4-methoxy-3-[(naphthalen-1-ylcarbonyl)oxy]phenyl)prop-2-enoyl]amino)benzoic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Staphylococcus aureus
3-([(2E)-2-cyano-3-(4-methoxy-3-[(naphthalen-1-ylcarbonyl)oxy]phenyl)prop-2-enoyl]amino)benzoic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Thermotoga maritima
5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Deinococcus radiodurans
5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Escherichia coli
5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Staphylococcus aureus
5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Thermotoga maritima
5-chloro-3-(2-oxo-2-(4-[3-(trifluoromethyl)phenyl]piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Deinococcus radiodurans
5-chloro-3-(2-oxo-2-(4-[3-(trifluoromethyl)phenyl]piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Escherichia coli
5-chloro-3-(2-oxo-2-(4-[3-(trifluoromethyl)phenyl]piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Staphylococcus aureus
5-chloro-3-(2-oxo-2-(4-[3-(trifluoromethyl)phenyl]piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Thermotoga maritima
ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Deinococcus radiodurans
ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Escherichia coli
ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Staphylococcus aureus
ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Thermotoga maritima
additional information structure-based design of enzyme Der inhibitors using the X-ray crystal structure of Thermotoga maritima Der, computer-aided pharmacophore modeling. Analysis of the interactions of the inhibitory compounds with the Der GTP-binding site to understand the mechanism of inhibition. No or poor inhibition by 3-[(4Z)-5-hydroxy-3-methyl-4-([5-(2-methyl-5-nitrophenyl)furan-2-yl]methylidene)-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 3-[(4Z)-4-([5-(3-acetylphenyl)furan-2-yl]methylidene)-5-hydroxy-3-methyl-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 2-((Z)-[3-(4-carboxyphenyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene]methyl)benzoic acid, (4E)-4-(2-[2-(3-methoxyphenoxy)ethoxy]benzylidene)-1-phenylpyrazolidine-3,5-dione, 3,4-bis([(3,4-dimethylphenoxy)acetyl]amino)benzoic acid, 2-(5,5-dimethyl-3-methylidenehexyl)-1-methyl-5-(3-adamantylbutyl)-3-propylbenzene, and 2-(3-([((2-[2-(dimethylamino)ethyl]-1H-indol-3-yl)methyl)sulfanyl]methyl)-5-methyl-1H-indol-2-yl)-N,N-dimethylethanamine Deinococcus radiodurans
additional information structure-based design of enzyme Der inhibitors using the X-ray crystal structure of Thermotoga maritima Der, computer-aided pharmacophore modeling. Analysis of the interactions of the inhibitory compounds with the Der GTP-binding site to understand the mechanism of inhibition. No or poor inhibition by 3-[(4Z)-5-hydroxy-3-methyl-4-([5-(2-methyl-5-nitrophenyl)furan-2-yl]methylidene)-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 3-[(4Z)-4-([5-(3-acetylphenyl)furan-2-yl]methylidene)-5-hydroxy-3-methyl-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 2-((Z)-[3-(4-carboxyphenyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene]methyl)benzoic acid, (4E)-4-(2-[2-(3-methoxyphenoxy)ethoxy]benzylidene)-1-phenylpyrazolidine-3,5-dione, 3,4-bis([(3,4-dimethylphenoxy)acetyl]amino)benzoic acid, 2-(5,5-dimethyl-3-methylidenehexyl)-1-methyl-5-(3-adamantylbutyl)-3-propylbenzene, and 2-(3-([((2-[2-(dimethylamino)ethyl]-1H-indol-3-yl)methyl)sulfanyl]methyl)-5-methyl-1H-indol-2-yl)-N,N-dimethylethanamine Escherichia coli
additional information structure-based design of enzyme Der inhibitors using the X-ray crystal structure of Thermotoga maritima Der, computer-aided pharmacophore modeling. Analysis of the interactions of the inhibitory compounds with the Der GTP-binding site to understand the mechanism of inhibition. No or poor inhibition by 3-[(4Z)-5-hydroxy-3-methyl-4-([5-(2-methyl-5-nitrophenyl)furan-2-yl]methylidene)-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 3-[(4Z)-4-([5-(3-acetylphenyl)furan-2-yl]methylidene)-5-hydroxy-3-methyl-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 2-((Z)-[3-(4-carboxyphenyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene]methyl)benzoic acid, (4E)-4-(2-[2-(3-methoxyphenoxy)ethoxy]benzylidene)-1-phenylpyrazolidine-3,5-dione, 3,4-bis([(3,4-dimethylphenoxy)acetyl]amino)benzoic acid, 2-(5,5-dimethyl-3-methylidenehexyl)-1-methyl-5-(3-adamantylbutyl)-3-propylbenzene, and 2-(3-([((2-[2-(dimethylamino)ethyl]-1H-indol-3-yl)methyl)sulfanyl]methyl)-5-methyl-1H-indol-2-yl)-N,N-dimethylethanamine Staphylococcus aureus
additional information structure-based design of enzyme Der inhibitors using the X-ray crystal structure of Thermotoga maritima Der, computer-aided pharmacophore modeling. Analysis of the interactions of the inhibitory compounds with the Der GTP-binding site to understand the mechanism of inhibition. No or poor inhibition by 3-[(4Z)-5-hydroxy-3-methyl-4-([5-(2-methyl-5-nitrophenyl)furan-2-yl]methylidene)-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 3-[(4Z)-4-([5-(3-acetylphenyl)furan-2-yl]methylidene)-5-hydroxy-3-methyl-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid, 2-((Z)-[3-(4-carboxyphenyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene]methyl)benzoic acid, (4E)-4-(2-[2-(3-methoxyphenoxy)ethoxy]benzylidene)-1-phenylpyrazolidine-3,5-dione, 3,4-bis([(3,4-dimethylphenoxy)acetyl]amino)benzoic acid, 2-(5,5-dimethyl-3-methylidenehexyl)-1-methyl-5-(3-adamantylbutyl)-3-propylbenzene, and 2-(3-([((2-[2-(dimethylamino)ethyl]-1H-indol-3-yl)methyl)sulfanyl]methyl)-5-methyl-1H-indol-2-yl)-N,N-dimethylethanamine Thermotoga maritima
N-(2-acetylphenyl)-4-([2-(4-chloro-2-methylphenoxy)propanoyl]amino)benzamide the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Deinococcus radiodurans
N-(2-acetylphenyl)-4-([2-(4-chloro-2-methylphenoxy)propanoyl]amino)benzamide the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Escherichia coli
N-(2-acetylphenyl)-4-([2-(4-chloro-2-methylphenoxy)propanoyl]amino)benzamide the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Staphylococcus aureus
N-(2-acetylphenyl)-4-([2-(4-chloro-2-methylphenoxy)propanoyl]amino)benzamide the compound is both biologically active against bacterial cells and a putative enzymatic inhibitor of Der GTPase homologue Thermotoga maritima

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required, binding structure analysis Staphylococcus aureus
Mg2+ required, binding structure analysis Thermotoga maritima
Mg2+ required, binding structure analysis Escherichia coli
Mg2+ required, binding structure analysis Deinococcus radiodurans

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
GTP + H2O Staphylococcus aureus
-
 GDP + phosphate
-
 ?
GTP + H2O Thermotoga maritima
-
 GDP + phosphate
-
 ?
GTP + H2O Escherichia coli
-
 GDP + phosphate
-
 ?
GTP + H2O Deinococcus radiodurans
-
 GDP + phosphate
-
 ?

Organism

Organism UniProt Comment Textmining
Deinococcus radiodurans Q9RS19
-
-
Escherichia coli P0A6P5
-
-
Staphylococcus aureus
-
-
-
Thermotoga maritima Q9X1F8
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant enzyme from Escherichia coli strain BL21(DE3) Thermotoga maritima
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography Staphylococcus aureus
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography Deinococcus radiodurans

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
GTP + H2O
-
 Staphylococcus aureus GDP + phosphate
-
 ?
GTP + H2O
-
 Thermotoga maritima GDP + phosphate
-
 ?
GTP + H2O
-
 Escherichia coli GDP + phosphate
-
 ?
GTP + H2O
-
 Deinococcus radiodurans GDP + phosphate
-
 ?
GTP + H2O GTP binds to Der in a cooperative manner and the interruption of cooperative nucleotide association disrupts the interaction of Der with the 50S subunit Staphylococcus aureus GDP + phosphate
-
 ?
GTP + H2O GTP binds to Der in a cooperative manner and the interruption of cooperative nucleotide association disrupts the interaction of Der with the 50S subunit Thermotoga maritima GDP + phosphate
-
 ?
GTP + H2O GTP binds to Der in a cooperative manner and the interruption of cooperative nucleotide association disrupts the interaction of Der with the 50S subunit Escherichia coli GDP + phosphate
-
 ?
GTP + H2O GTP binds to Der in a cooperative manner and the interruption of cooperative nucleotide association disrupts the interaction of Der with the 50S subunit Deinococcus radiodurans GDP + phosphate
-
 ?

Subunits

Subunits Comment Organism
More Der has a C-terminal KH-like (RNA-binding module-like) domain flanked by two tandemly repeated GTP-binding domains at the N-terminus Staphylococcus aureus
More Der has a C-terminal KH-like (RNA-binding module-like) domain flanked by two tandemly repeated GTP-binding domains at the N-terminus Thermotoga maritima
More Der has a C-terminal KH-like (RNA-binding module-like) domain flanked by two tandemly repeated GTP-binding domains at the N-terminus Escherichia coli
More Der has a C-terminal KH-like (RNA-binding module-like) domain flanked by two tandemly repeated GTP-binding domains at the N-terminus Deinococcus radiodurans

Synonyms

Synonyms Comment Organism
Der
-
 Staphylococcus aureus
Der
-
 Thermotoga maritima
Der
-
 Escherichia coli
Der
-
 Deinococcus radiodurans
Der GTPase
-
 Staphylococcus aureus
Der GTPase
-
 Thermotoga maritima
Der GTPase
-
 Escherichia coli
Der GTPase
-
 Deinococcus radiodurans
double Era-like protein
-
 Staphylococcus aureus
double Era-like protein
-
 Thermotoga maritima
double Era-like protein
-
 Escherichia coli
double Era-like protein
-
 Deinococcus radiodurans

General Information

General Information Comment Organism
additional information each of the two Der GTP-binding domains expressed separately has an intrinsic GTPase activity, though the activity of the N-terminal GD1 domain is stronger than that of the GD2 domain Thermotoga maritima
physiological function enzyme Der is an essential and widely conserved GTPase that assists assembly of a large ribosomal subunit in bacteria. Enzyme Der associates specifically with the 50S subunit in a GTP-dependent manner and the cells depleted of GTPase Der accumulate the structurally unstable 50S subunit, which dissociates into an aberrant subunit at a lower Mg2+ concentration. The enzyme Der is an essential and ubiquitous protein in bacteria Staphylococcus aureus
physiological function enzyme Der is an essential and widely conserved GTPase that assists assembly of a large ribosomal subunit in bacteria. Enzyme Der associates specifically with the 50S subunit in a GTP-dependent manner and the cells depleted of GTPase Der accumulate the structurally unstable 50S subunit, which dissociates into an aberrant subunit at a lower Mg2+ concentration. The enzyme Der is an essential and ubiquitous protein in bacteria Thermotoga maritima
physiological function enzyme Der is an essential and widely conserved GTPase that assists assembly of a large ribosomal subunit in bacteria. Enzyme Der associates specifically with the 50S subunit in a GTP-dependent manner and the cells depleted of GTPase Der accumulate the structurally unstable 50S subunit, which dissociates into an aberrant subunit at a lower Mg2+ concentration. The enzyme Der is an essential and ubiquitous protein in bacteria Escherichia coli
physiological function enzyme Der is an essential and widely conserved GTPase that assists assembly of a large ribosomal subunit in bacteria. Enzyme Der associates specifically with the 50S subunit in a GTP-dependent manner and the cells depleted of GTPase Der accumulate the structurally unstable 50S subunit, which dissociates into an aberrant subunit at a lower Mg2+ concentration. The enzyme Der is an essential and ubiquitous protein in bacteria Deinococcus radiodurans