1erm

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[[Image:1erm.jpg|left|200px]]<br /><applet load="1erm" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1erm, resolution 1.70&Aring;" />
 
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'''X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-1-ACETAMIDO-2-(3-CARBOXYPHENYL)ETHANE BORONIC ACID'''<br />
 
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==Overview==
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==X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-1-ACETAMIDO-2-(3-CARBOXYPHENYL)ETHANE BORONIC ACID==
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Transition state analogue boronic acid inhibitors mimicking the structures and interactions of good penicillin substrates for the TEM-1 beta-lactamase of Escherchia coli were designed using graphic analyses based on the enzyme's 1.7 A crystallographic structure. The synthesis of two of these transition state analogues, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1) and (1R)-1-acetamido-2-(3-carboxy-2-hydroxyphenyl)ethylboronic acid (2), is reported. Kinetic measurements show that, as designed, compounds 1 and 2 are highly effective deacylation transition state analogue inhibitors of TEM-1 beta-lactamase, with inhibition constants of 5.9 and 13 nM, respectively. These values identify them as among the most potent competitive inhibitors yet reported for a beta-lactamase. The best inhibitor of the current series was (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1, K(I) = 5.9 nM), which resembles most closely the best known substrate of TEM-1, benzylpenicillin (penicillin G). The high-resolution crystallographic structures of these two inhibitors covalently bound to TEM-1 are also described. In addition to verifying the design features, these two structures show interesting and unanticipated changes in the active site area, including strong hydrogen bond formation, water displacement, and rearrangement of side chains. The structures provide new insights into the further design of this potent class of beta-lactamase inhibitors.
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<StructureSection load='1erm' size='340' side='right'caption='[[1erm]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1erm]] is a 1 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=1ERM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ERM FirstGlance]. <br>
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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]] 1.7&#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=BHD:(3S)-3-HYDROXY-L-ASPARTIC+ACID'>BHD</scene>, <scene name='pdbligand=BJI:1(R)-1-ACETAMIDO-2-(3-CARBOXYPHENYL)ETHYL+BORONIC+ACID'>BJI</scene></td></tr>
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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=1erm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1erm OCA], [https://pdbe.org/1erm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1erm RCSB], [https://www.ebi.ac.uk/pdbsum/1erm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1erm ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/BLAT_ECOLX BLAT_ECOLX] TEM-type are the most prevalent beta-lactamases in enterobacteria; they hydrolyze the beta-lactam bond in susceptible beta-lactam antibiotics, thus conferring resistance to penicillins and cephalosporins. TEM-3 and TEM-4 are capable of hydrolyzing cefotaxime and ceftazidime. TEM-5 is capable of hydrolyzing ceftazidime. TEM-6 is capable of hydrolyzing ceftazidime and aztreonam. TEM-8/CAZ-2, TEM-16/CAZ-7 and TEM-24/CAZ-6 are markedly active against ceftazidime. IRT-4 shows resistance to beta-lactamase inhibitors.
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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/er/1erm_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=1erm ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1ERM 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 <scene name='pdbligand=BJI:'>BJI</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ERM OCA].
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*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Structure-based design guides the improved efficacy of deacylation transition state analogue inhibitors of TEM-1 beta-Lactamase(,)., Ness S, Martin R, Kindler AM, Paetzel M, Gold M, Jensen SE, Jones JB, Strynadka NC, Biochemistry. 2000 May 9;39(18):5312-21. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10820001 10820001]
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[[Category: Beta-lactamase]]
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[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Gold, M.]]
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[[Category: Gold M]]
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[[Category: Jones, J B.]]
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[[Category: Jones JB]]
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[[Category: Kindler, A M.]]
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[[Category: Kindler AM]]
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[[Category: Martin, R.]]
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[[Category: Martin R]]
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[[Category: Ness, S.]]
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[[Category: Ness S]]
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[[Category: Paetzel, M.]]
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[[Category: Paetzel M]]
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[[Category: Strynadka, N C.J.]]
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[[Category: Strynadka NCJ]]
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[[Category: BJI]]
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[[Category: beta-lactamase]]
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[[Category: boronate inhibitor]]
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[[Category: structure-based design]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:30:49 2008''
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Current revision

X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-1-ACETAMIDO-2-(3-CARBOXYPHENYL)ETHANE BORONIC ACID

PDB ID 1erm

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