5ewa: Difference between revisions
No edit summary |
No edit summary |
||
| Line 6: | Line 6: | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9BZ:(3~{R},5~{R},7~{A}~{S})-2,2-DIMETHYL-5-(SULFANYLMETHYL)-3,5,7,7~{A}-TETRAHYDRO-[1,3]THIAZOLO[4,3-B][1,3]THIAZOLE-3-CARBOXYLIC+ACID'>9BZ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9BZ:(3~{R},5~{R},7~{A}~{S})-2,2-DIMETHYL-5-(SULFANYLMETHYL)-3,5,7,7~{A}-TETRAHYDRO-[1,3]THIAZOLO[4,3-B][1,3]THIAZOLE-3-CARBOXYLIC+ACID'>9BZ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ewa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ewa OCA], [http://pdbe.org/5ewa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ewa RCSB], [http://www.ebi.ac.uk/pdbsum/5ewa PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ewa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ewa OCA], [http://pdbe.org/5ewa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ewa RCSB], [http://www.ebi.ac.uk/pdbsum/5ewa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ewa ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/BLAB_SERMA BLAB_SERMA]] Confers resistance to imipenem and broad-spectrum beta-lactams. Also hydrolyzes carbapenems. | [[http://www.uniprot.org/uniprot/BLAB_SERMA BLAB_SERMA]] Confers resistance to imipenem and broad-spectrum beta-lactams. Also hydrolyzes carbapenems. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Metallo-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<ref>PMID:27303030</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5ewa" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 09:24, 26 July 2016
Crystal structure of the metallo-beta-lactamase IMP-1 in complex with the bisthiazolidine inhibitor L-VC26Crystal structure of the metallo-beta-lactamase IMP-1 in complex with the bisthiazolidine inhibitor L-VC26
Structural highlights
Function[BLAB_SERMA] Confers resistance to imipenem and broad-spectrum beta-lactams. Also hydrolyzes carbapenems. 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. References
|
| ||||||||||||||||||