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Literature summary 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

Application

EC Number Application Comment Organism
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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)

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

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
3.6.5.2 crystal structure analysis, PDB ID 1MKY, computer-aided pharmacophore modeling and modeling of GTP and GDP binding to the enzyme, overview Thermotoga maritima
3.6.5.2 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

EC Number Inhibitors Comment Organism Structure
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Deinococcus radiodurans
3.6.5.2 5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Escherichia coli
3.6.5.2 5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Staphylococcus aureus
3.6.5.2 5-(3-chloro-4-[(3-fluorobenzyl)oxy]-5-methoxybenzyl)-1-(4-hydroxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Thermotoga maritima
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Deinococcus radiodurans
3.6.5.2 ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Escherichia coli
3.6.5.2 ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Staphylococcus aureus
3.6.5.2 ethyl ([2-(2-methoxy-4-((Z)-[1-(4-methylphenyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl)phenoxy)ethyl]sulfanyl)acetate
-
 Thermotoga maritima
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining

Metals/Ions

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

Natural Substrates/ Products (Substrates)

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

Organism

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

Purification (Commentary)

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

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.6.5.2 GTP + H2O
-
 Staphylococcus aureus GDP + phosphate
-
 ?
3.6.5.2 GTP + H2O
-
 Thermotoga maritima GDP + phosphate
-
 ?
3.6.5.2 GTP + H2O
-
 Escherichia coli GDP + phosphate
-
 ?
3.6.5.2 GTP + H2O
-
 Deinococcus radiodurans GDP + phosphate
-
 ?
3.6.5.2 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
-
 ?
3.6.5.2 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
-
 ?
3.6.5.2 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
-
 ?
3.6.5.2 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

EC Number Subunits Comment Organism
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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

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

General Information

EC Number General Information Comment Organism
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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
3.6.5.2 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