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1my8

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[[Image:1my8.jpg|left|200px]]<br /><applet load="1my8" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1my8, resolution 1.72&Aring;" />
 
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'''AmpC beta-lactamase in complex with an M.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain'''<br />
 
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==Overview==
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==AmpC beta-lactamase in complex with an M.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain==
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beta-lactamases are the most widespread resistance mechanism to beta-lactam antibiotics, such as the penicillins and the cephalosporins. In an effort to combat these enzymes, a combination of stereoselective organic synthesis, enzymology, microbiology, and X-ray crystallography was used to design and evaluate new carboxyphenyl-glycylboronic acid transition-state analogue inhibitors of the class C beta-lactamase AmpC. The new compounds improve inhibition by over 2 orders of magnitude compared to analogous glycylboronic acids, with K(i) values as low as 1 nM. On the basis of the differential binding of different analogues, the introduced carboxylate alone contributes about 2.1 kcal/mol in affinity. This carboxylate corresponds to the ubiquitous C3(4)' carboxylate of beta-lactams, and this energy represents the first thermodynamic measurement of the importance of this group in molecular recognition by class C beta-lactamases. The structures of AmpC in complex with two of these inhibitors were determined by X-ray crystallography at 1.72 and 1.83 A resolution. These structures suggest a structural basis for the high affinity of the new compounds and provide templates for further design. The highest affinity inhibitor was 5 orders of magnitude more selective for AmpC than for characteristic serine proteases, such as chymotrypsin. This inhibitor reversed the resistance of clinical pathogens to the third generation cephalosporin ceftazidime; it may serve as a lead compound for drug discovery to combat bacterial resistance to beta-lactam antibiotics.
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<StructureSection load='1my8' size='340' side='right'caption='[[1my8]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1my8]] is a 2 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=1MY8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1MY8 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]] 1.72&#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=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SM3:(1R)-1-(2-THIENYLACETYLAMINO)-1-PHENYLMETHYLBORONIC+ACID'>SM3</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=1my8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1my8 OCA], [https://pdbe.org/1my8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1my8 RCSB], [https://www.ebi.ac.uk/pdbsum/1my8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1my8 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
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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/my/1my8_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=1my8 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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1MY8 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=PO4:'>PO4</scene> and <scene name='pdbligand=SM3:'>SM3</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1MY8 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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Nanomolar inhibitors of AmpC beta-lactamase., Morandi F, Caselli E, Morandi S, Focia PJ, Blazquez J, Shoichet BK, Prati F, J Am Chem Soc. 2003 Jan 22;125(3):685-95. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12526668 12526668]
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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: Blazquez, J.]]
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[[Category: Blazquez J]]
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[[Category: Caselli, E.]]
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[[Category: Caselli E]]
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[[Category: Focia, P J.]]
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[[Category: Focia PJ]]
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[[Category: Morandi, F.]]
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[[Category: Morandi F]]
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[[Category: Morandi, S.]]
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[[Category: Morandi S]]
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[[Category: Prati, F.]]
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[[Category: Prati F]]
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[[Category: Shoichet, B K.]]
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[[Category: Shoichet BK]]
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[[Category: PO4]]
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[[Category: SM3]]
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[[Category: ampc]]
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[[Category: beta-lactamase]]
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[[Category: cephalosporinase]]
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[[Category: serine hydrolase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:00:17 2008''
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Current revision

AmpC beta-lactamase in complex with an M.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain

PDB ID 1my8

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