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| | <StructureSection load='5ew0' size='340' side='right'caption='[[5ew0]], [[Resolution|resolution]] 1.30Å' scene=''> | | <StructureSection load='5ew0' size='340' side='right'caption='[[5ew0]], [[Resolution|resolution]] 1.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ew0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Atcc_29844 Atcc 29844]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EW0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EW0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ew0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Serratia_fonticola Serratia fonticola]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EW0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EW0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3C7:(3R,5R,7AS)-5-(SULFANYLMETHYL)TETRAHYDRO[1,3]THIAZOLO[4,3-B][1,3]THIAZOLE-3-CARBOXYLIC+ACID'>3C7</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">sfhI ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=47917 ATCC 29844])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3C7:(3R,5R,7AS)-5-(SULFANYLMETHYL)TETRAHYDRO[1,3]THIAZOLO[4,3-B][1,3]THIAZOLE-3-CARBOXYLIC+ACID'>3C7</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'>[https://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=5ew0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ew0 OCA], [https://pdbe.org/5ew0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ew0 RCSB], [https://www.ebi.ac.uk/pdbsum/5ew0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ew0 ProSAT]</span></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=5ew0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ew0 OCA], [https://pdbe.org/5ew0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ew0 RCSB], [https://www.ebi.ac.uk/pdbsum/5ew0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ew0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q9RMI1_SERFO Q9RMI1_SERFO] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Atcc 29844]] | |
| - | [[Category: Beta-lactamase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Hinchliffe, P]] | + | [[Category: Serratia fonticola]] |
| - | [[Category: Spencer, J]] | + | [[Category: Hinchliffe P]] |
| - | [[Category: Tooke, C L]] | + | [[Category: Spencer J]] |
| - | [[Category: Antibiotic resistance]] | + | [[Category: Tooke CL]] |
| - | [[Category: Carbapenemase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| Structural highlights
Function
Q9RMI1_SERFO
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Cross-class metallo-beta-lactamase inhibition by bisthiazolidines reveals multiple binding modes. 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 doi:http://dx.doi.org/10.1073/pnas.1601368113
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