1g2a

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(New page: 200px<br /><applet load="1g2a" size="450" color="white" frame="true" align="right" spinBox="true" caption="1g2a, resolution 1.75&Aring;" /> '''THE CRYSTAL STRUCTUR...)
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[[Image:1g2a.gif|left|200px]]<br /><applet load="1g2a" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1g2a, resolution 1.75&Aring;" />
 
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'''THE CRYSTAL STRUCTURE OF E.COLI PEPTIDE DEFORMYLASE COMPLEXED WITH ACTINONIN'''<br />
 
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==Overview==
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==THE CRYSTAL STRUCTURE OF E.COLI PEPTIDE DEFORMYLASE COMPLEXED WITH ACTINONIN==
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Peptide deformylase (PDF) is an essential bacterial metalloenzyme which, deformylates the N-formylmethionine of newly synthesized polypeptides and, as such represents a novel target for antibacterial chemotherapy. To, identify novel PDF inhibitors, we screened a metalloenzyme inhibitor, library and identified an N-formyl-hydroxylamine derivative, BB-3497, and, a related natural hydroxamic acid antibiotic, actinonin, as potent and, selective inhibitors of PDF. To elucidate the interactions that contribute, to the binding affinity of these inhibitors, we determined the crystal, structures of BB-3497 and actinonin bound to Escherichia coli PDF at, resolutions of 2.1 and 1.75 A, respectively. In both complexes, the, active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or, hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and, vancomycin-resistant Enterococcus faecalis, and activity against some, gram-negative bacteria. Time-kill analysis showed that the mode of action, of BB-3497 was primarily bacteriostatic. The mechanism of resistance was, via mutations within the formyltransferase gene, as previously described, for actinonin. While actinonin and its derivatives have not been used, clinically because of their poor pharmacokinetic properties, BB-3497 was, shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h, after intraperitoneal injection of S. aureus Smith or, methicillin-resistant S. aureus protected mice from infection with median, effective doses of 8 and 14 mg/kg of body weight, respectively. These data, validate PDF as a novel target for the design of a new generation of, antibacterial agents.
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<StructureSection load='1g2a' size='340' side='right'caption='[[1g2a]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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== Structural highlights ==
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==About this Structure==
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<table><tr><td colspan='2'>[[1g2a]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1G2A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1G2A FirstGlance]. <br>
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1G2A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with NI and BB2 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Formylmethionine_deformylase Formylmethionine deformylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.31 3.5.1.31] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1G2A OCA].
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BB2:ACTINONIN'>BB2</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
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==Reference==
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1g2a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1g2a OCA], [https://pdbe.org/1g2a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1g2a RCSB], [https://www.ebi.ac.uk/pdbsum/1g2a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1g2a ProSAT]</span></td></tr>
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Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor., Clements JM, Beckett RP, Brown A, Catlin G, Lobell M, Palan S, Thomas W, Whittaker M, Wood S, Salama S, Baker PJ, Rodgers HF, Barynin V, Rice DW, Hunter MG, Antimicrob Agents Chemother. 2001 Feb;45(2):563-70. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11158755 11158755]
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DEF_ECOLI DEF_ECOLI] Removes the formyl group from the N-terminal Met of newly synthesized proteins. Requires at least a dipeptide for an efficient rate of reaction. N-terminal L-methionine is a prerequisite for activity but the enzyme has broad specificity at other positions.[HAMAP-Rule:MF_00163]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g2/1g2a_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1g2a ConSurf].
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<div style="clear:both"></div>
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__TOC__
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</StructureSection>
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
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[[Category: Formylmethionine deformylase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Baker PJ]]
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[[Category: Baker, P.J.]]
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[[Category: Barynin V]]
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[[Category: Barynin, V.]]
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[[Category: Beckett P]]
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[[Category: Beckett, P.]]
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[[Category: Brown A]]
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[[Category: Brown, A.]]
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[[Category: Catlin C]]
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[[Category: Catlin, C.]]
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[[Category: Clements JM]]
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[[Category: Clements, J.M.]]
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[[Category: Hunter MG]]
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[[Category: Hunter, M.G.]]
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[[Category: Lobell M]]
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[[Category: Lobell, M.]]
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[[Category: Palan S]]
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[[Category: Palan, S.]]
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[[Category: Rice DW]]
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[[Category: Rice, D.W.]]
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[[Category: Rodgers HF]]
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[[Category: Rodgers, H.F.]]
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[[Category: Thomas W]]
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[[Category: Thomas, W.]]
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[[Category: Whittaker M]]
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[[Category: Whittaker, M.]]
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[[Category: BB2]]
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[[Category: NI]]
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[[Category: actinonin]]
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[[Category: inhibition]]
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[[Category: polypeptide deformylase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 15:38:28 2007''
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Current revision

THE CRYSTAL STRUCTURE OF E.COLI PEPTIDE DEFORMYLASE COMPLEXED WITH ACTINONIN

PDB ID 1g2a

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