General Information of the Molecule (ID: Mol00952)
Name
Elongation factor Tu 1 (TUFA) ,Escherichia coli
Synonyms
EF-Tu 1; Bacteriophage Q beta RNA-directed RNA polymerase subunit III; P-43; b3339; JW3301
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Molecule Type
Protein
Gene Name
tufA
Gene ID
66672781
Sequence
MSKEKFERTKPHVNVGTIGHVDHGKTTLTAAITTVLAKTYGGAARAFDQIDNAPEEKARG
ITINTSHVEYDTPTRHYAHVDCPGHADYVKNMITGAAQMDGAILVVAATDGPMPQTREHI
LLGRQVGVPYIIVFLNKCDMVDDEELLELVEMEVRELLSQYDFPGDDTPIVRGSALKALE
GDAEWEAKILELAGFLDSYIPEPERAIDKPFLLPIEDVFSISGRGTVVTGRVERGIIKVG
EEVEIVGIKETQKSTCTGVEMFRKLLDEGRAGENVGVLLRGIKREEIERGQVLAKPGTIK
PHTKFESEVYILSKDEGGRHTPFFKGYRPQFYFRTTDVTGTIELPEGVEMVMPGDNIKMV
VTLIHPIAMDDGLRFAIREGGRTVGAGVVAKVLG
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Function
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.; FUNCTION: May play an important regulatory role in cell growth and in the bacterial response to nutrient deprivation.; FUNCTION: Plays a stimulatory role in trans-translation; binds tmRNA.
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Uniprot ID
EFTU1_ECOLI
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Kingdom: N.A.
Phylum: Proteobacteria
Class: Gammaproteobacteria
Order: Enterobacterales
Family: Enterobacteriaceae
Genus: Escherichia
Species: Escherichia coli
Type(s) of Resistant Mechanism of This Molecule
  ADTT: Aberration of the Drug's Therapeutic Target
Drug Resistance Data Categorized by Drug
Investigative Drug(s)
3 drug(s) in total
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Ge2270a
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Escherichia coli infection [1]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Ge2270a
Molecule Alteration Missense mutation
p.G257S
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain 562
Mechanism Description The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.
Disease Class: Escherichia coli infection [1]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Ge2270a
Molecule Alteration Missense mutation
p.G275A
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain 562
Mechanism Description The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.
Kirromycin
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Escherichia coli infection [2], [3], [4]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Kirromycin
Molecule Alteration Mutantion
p.G316D
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
Escherichia coli strain MRE600 562
Experiment for
Molecule Alteration
Whole genome sequence assay
Mechanism Description The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.
Disease Class: Escherichia coli infection [2], [3], [4]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Kirromycin
Molecule Alteration Mutantion
p.A375T
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
Escherichia coli strain MRE600 562
Experiment for
Molecule Alteration
Whole genome sequence assay
Mechanism Description The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.
Disease Class: Escherichia coli infection [2], [3], [4]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Kirromycin
Molecule Alteration Mutantion
p.A375V
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
Escherichia coli strain MRE600 562
Experiment for
Molecule Alteration
Whole genome sequence assay
Mechanism Description The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.
Disease Class: Escherichia coli infection [2], [3], [4]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Kirromycin
Molecule Alteration Mutantion
p.Q124K
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
Escherichia coli strain MRE600 562
Experiment for
Molecule Alteration
Whole genome sequence assay
Mechanism Description The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.
Pulvomycin
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Escherichia coli infection [5]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Pulvomycin
Molecule Alteration Missense mutation
p.R230C
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain LZ33L 562
Escherichiacoli strain EV4 562
Escherichiacoli strain LBE2040 562
Escherichiacoli strain LZ32L 562
Escherichiacoli strain LZ35L 562
Escherichiacoli strain LZ36L 562
Escherichiacoli strain LZ37L 562
Escherichiacoli strain MG1655 511145
Experiment for
Drug Resistance
MIC assay
Mechanism Description Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.
Disease Class: Escherichia coli infection [5]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Pulvomycin
Molecule Alteration Missense mutation
p.R333C
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain LZ33L 562
Escherichiacoli strain EV4 562
Escherichiacoli strain LBE2040 562
Escherichiacoli strain LZ32L 562
Escherichiacoli strain LZ35L 562
Escherichiacoli strain LZ36L 562
Escherichiacoli strain LZ37L 562
Escherichiacoli strain MG1655 511145
Experiment for
Drug Resistance
MIC assay
Mechanism Description Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.
Disease Class: Escherichia coli infection [5]
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
Resistant Drug Pulvomycin
Molecule Alteration Missense mutation
p.T334A
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain LZ33L 562
Escherichiacoli strain EV4 562
Escherichiacoli strain LBE2040 562
Escherichiacoli strain LZ32L 562
Escherichiacoli strain LZ35L 562
Escherichiacoli strain LZ36L 562
Escherichiacoli strain LZ37L 562
Escherichiacoli strain MG1655 511145
Experiment for
Drug Resistance
MIC assay
Mechanism Description Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.
References
Ref 1 GE2270A-resistant mutations in elongation factor Tu allow productive aminoacyl-tRNA binding to EF-Tu.GTP.GE2270A complexes. J Mol Biol. 2000 Dec 15;304(5):995-1005. doi: 10.1006/jmbi.2000.4260.
Ref 2 Inhibitory mechanisms of antibiotics targeting elongation factor Tu. Curr Protein Pept Sci. 2002 Feb;3(1):121-31. doi: 10.2174/1389203023380855.
Ref 3 Mutant sequences in the rpsL gene of Escherichia coli B/r: mechanistic implications for spontaneous and ultraviolet light mutagenesis. Mol Gen Genet. 1992 Mar;232(1):89-96. doi: 10.1007/BF00299141.
Ref 4 The structural and functional basis for the kirromycin resistance of mutant EF-Tu species in Escherichia coli. EMBO J. 1994 Oct 17;13(20):4877-85.
Ref 5 Pulvomycin-resistant mutants of E.coli elongation factor Tu. EMBO J. 1994 Nov 1;13(21):5113-20.

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