1c3b

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[[Image:1c3b.gif|left|200px]]<br /><applet load="1c3b" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1c3b, resolution 2.25&Aring;" />
 
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'''AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)'''<br />
 
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==Overview==
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==AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)==
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Beta-lactamases are the major resistance mechanism to beta-lactam antibiotics and pose a growing threat to public health. Recently, bacteria have become resistant to beta-lactamase inhibitors, making this problem pressing. In an effort to overcome this resistance, non-beta-lactam inhibitors of beta-lactamases were investigated for complementarity to the structure of AmpC beta-lactamase from Escherichia coli. This led to the discovery of an inhibitor, benzo(b)thiophene-2-boronic acid (BZBTH2B), which inhibited AmpC with a Ki of 27 nM. This inhibitor is chemically dissimilar to beta-lactams, raising the question of what specific interactions are responsible for its activity. To answer this question, the X-ray crystallographic structure of BZBTH2B in complex with AmpC was determined to 2.25 A resolution. The structure reveals several unexpected interactions. The inhibitor appears to complement the conserved, R1-amide binding region of AmpC, despite lacking an amide group. Interactions between one of the boronic acid oxygen atoms, Tyr150, and an ordered water molecule suggest a mechanism for acid/base catalysis and a direction for hydrolytic attack in the enzyme catalyzed reaction. To investigate how a non-beta-lactam inhibitor would perform against resistant bacteria, BZBTH2B was tested in antimicrobial assays. BZBTH2B significantly potentiated the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria. This inhibitor was unaffected by two common resistance mechanisms that often arise against beta-lactams in conjunction with beta-lactamases. Porin channel mutations did not decrease the efficacy of BZBTH2B against cells expressing AmpC. Also, this inhibitor did not induce expression of AmpC, a problem with many beta-lactams. The structure of the BZBTH2B/AmpC complex provides a starting point for the structure-based elaboration of this class of non-beta-lactam inhibitors.
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<StructureSection load='1c3b' size='340' side='right'caption='[[1c3b]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
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== Structural highlights ==
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==About this Structure==
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<table><tr><td colspan='2'>[[1c3b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C3B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1C3B FirstGlance]. <br>
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1C3B 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=BZB:'>BZB</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=1C3B 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]] 2.25&#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=BZB:BENZO[B]THIOPHENE-2-BORONIC+ACID'>BZB</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=1c3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c3b OCA], [https://pdbe.org/1c3b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1c3b RCSB], [https://www.ebi.ac.uk/pdbsum/1c3b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1c3b ProSAT]</span></td></tr>
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The complexed structure and antimicrobial activity of a non-beta-lactam inhibitor of AmpC beta-lactamase., Powers RA, Blazquez J, Weston GS, Morosini MI, Baquero F, Shoichet BK, Protein Sci. 1999 Nov;8(11):2330-7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10595535 10595535]
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</table>
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[[Category: Beta-lactamase]]
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== Function ==
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[[Category: Escherichia coli]]
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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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[[Category: Single protein]]
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== Evolutionary Conservation ==
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[[Category: Baquero, F.]]
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[[Image:Consurf_key_small.gif|200px|right]]
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[[Category: Blazquez, J.]]
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Check<jmol>
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[[Category: Morosini, M I.]]
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<jmolCheckbox>
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[[Category: Powers, R A.]]
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c3/1c3b_consurf.spt"</scriptWhenChecked>
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[[Category: Shoichet, B K.]]
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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[[Category: Weston, G S.]]
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<text>to colour the structure by Evolutionary Conservation</text>
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[[Category: BZB]]
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</jmolCheckbox>
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[[Category: beta-lactamase]]
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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=1c3b ConSurf].
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[[Category: cephalosporinase]]
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<div style="clear:both"></div>
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[[Category: serine hydrolase]]
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__TOC__
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</StructureSection>
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:01:56 2008''
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[[Category: Escherichia coli K-12]]
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[[Category: Large Structures]]
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[[Category: Baquero F]]
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[[Category: Blazquez J]]
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[[Category: Morosini MI]]
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[[Category: Powers RA]]
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[[Category: Shoichet BK]]
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[[Category: Weston GS]]

Current revision

AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)

PDB ID 1c3b

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