5evd: Difference between revisions
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==Crystal structure of the metallo-beta-lactamase L1 in complex with the bisthiazolidine inhibitor D-VC26== | ==Crystal structure of the metallo-beta-lactamase L1 in complex with the bisthiazolidine inhibitor D-VC26== | ||
<StructureSection load='5evd' size='340' side='right' caption='[[5evd]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='5evd' size='340' side='right'caption='[[5evd]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5evd]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EVD OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5evd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Stenotrophomonas_maltophilia Stenotrophomonas maltophilia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EVD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EVD FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VC2:(3S,5S,7AR)-2,2-DIMETHYL-5-(SULFANYLMETHYL)TETRAHYDRO[1,3]THIAZOLO[4,3-B][1,3]THIAZOLE-3-CARBOXYLIC+ACID'>VC2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VC2:(3S,5S,7AR)-2,2-DIMETHYL-5-(SULFANYLMETHYL)TETRAHYDRO[1,3]THIAZOLO[4,3-B][1,3]THIAZOLE-3-CARBOXYLIC+ACID'>VC2</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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5evd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5evd OCA], [https://pdbe.org/5evd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5evd RCSB], [https://www.ebi.ac.uk/pdbsum/5evd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5evd ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/BLA1_STEMA BLA1_STEMA] Has a high activity against imipenem. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5evd" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5evd" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Stenotrophomonas maltophilia]] | ||
[[Category: | [[Category: Hinchliffe P]] | ||
[[Category: | [[Category: Spencer J]] | ||
Latest revision as of 14:20, 3 January 2024
Crystal structure of the metallo-beta-lactamase L1 in complex with the bisthiazolidine inhibitor D-VC26Crystal structure of the metallo-beta-lactamase L1 in complex with the bisthiazolidine inhibitor D-VC26
Structural highlights
FunctionBLA1_STEMA Has a high activity against imipenem. Publication Abstract from PubMedMetallo-beta-lactamases (MBLs) hydrolyze almost all beta-lactam antibiotics and are unaffected by clinically available beta-lactamase inhibitors (betaLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of betaLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both l- and d-BTZ enantiomers are micromolar competitive betaLIs of all MBL classes in vitro, with Kis of 6-15 microM or 36-84 microM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 microM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the l-BTZ enantiomers exhibit 100-fold lower Kis (0.26-0.36 microM) than d-BTZs (26-29 microM). Importantly, cell-based time-kill assays show BTZs restore beta-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate beta-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the l-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. d-BTZ complexes most closely resemble beta-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding. Cross-class metallo-beta-lactamase inhibition by bisthiazolidines reveals multiple binding modes.,Hinchliffe P, Gonzalez MM, Mojica MF, Gonzalez JM, Castillo V, Saiz C, Kosmopoulou M, Tooke CL, Llarrull LI, Mahler G, Bonomo RA, Vila AJ, Spencer J Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3745-54. doi:, 10.1073/pnas.1601368113. Epub 2016 Jun 14. PMID:27303030[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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