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[[Image:1a8t.gif|left|200px]]<br /><applet load="1a8t" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1a8t, resolution 2.55&Aring;" />
'''METALLO-BETA-LACTAMASE IN COMPLEX WITH L-159,061'''<br />


==Overview==
==METALLO-BETA-LACTAMASE IN COMPLEX WITH L-159,061==
<StructureSection load='1a8t' size='340' side='right'caption='[[1a8t]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1a8t]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacteroides_fragilis Bacteroides fragilis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A8T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1A8T FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=061:2-BUTYL-6-HYDROXY-3-[2-(1H-TETRAZOL-5-YL)-BIPHENYL-4-YLMETHYL]-3H-QUINAZOLIN-4-ONE'>061</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1a8t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1a8t OCA], [https://pdbe.org/1a8t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1a8t RCSB], [https://www.ebi.ac.uk/pdbsum/1a8t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1a8t ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/BLAB_BACFG BLAB_BACFG] Can hydrolyze carbapenem compounds.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a8/1a8t_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=1a8t ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.
BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.


==About this Structure==
Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase.,Toney JH, Fitzgerald PM, Grover-Sharma N, Olson SH, May WJ, Sundelof JG, Vanderwall DE, Cleary KA, Grant SK, Wu JK, Kozarich JW, Pompliano DL, Hammond GG Chem Biol. 1998 Apr;5(4):185-96. PMID:9545432<ref>PMID:9545432</ref>
1A8T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_fragilis Bacteroides fragilis] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=061:'>061</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=1A8T OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase., Toney JH, Fitzgerald PM, Grover-Sharma N, Olson SH, May WJ, Sundelof JG, Vanderwall DE, Cleary KA, Grant SK, Wu JK, Kozarich JW, Pompliano DL, Hammond GG, Chem Biol. 1998 Apr;5(4):185-96. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9545432 9545432]
</div>
<div class="pdbe-citations 1a8t" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bacteroides fragilis]]
[[Category: Bacteroides fragilis]]
[[Category: Beta-lactamase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Fitzgerald PMD]]
[[Category: Fitzgerald, P M.D.]]
[[Category: Grover N]]
[[Category: Grover, N.]]
[[Category: Toney JH]]
[[Category: Toney, J H.]]
[[Category: Vanderwall D]]
[[Category: Vanderwall, D.]]
[[Category: 061]]
[[Category: ZN]]
[[Category: antibiotic resistance]]
[[Category: beta-lactamase]]
[[Category: hydrolase]]
[[Category: metallo-beta-lactamase]]
[[Category: zinc]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:42:13 2008''

Latest revision as of 10:49, 2 August 2023

METALLO-BETA-LACTAMASE IN COMPLEX WITH L-159,061

1a8t, resolution 2.55Å

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