6tgd: Difference between revisions
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==Crystal structure of NDM-1 in complex with triazole-based inhibitor OP31== | ==Crystal structure of NDM-1 in complex with triazole-based inhibitor OP31== | ||
<StructureSection load='6tgd' size='340' side='right'caption='[[6tgd]]' scene=''> | <StructureSection load='6tgd' size='340' side='right'caption='[[6tgd]], [[Resolution|resolution]] 1.33Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TGD OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6tgd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TGD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TGD FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.33Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=N8Q:4-[[(2~{S})-oxolan-2-yl]methyl]-3-pyridin-3-yl-1~{H}-1,2,4-triazole-5-thione'>N8Q</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=6tgd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tgd OCA], [https://pdbe.org/6tgd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tgd RCSB], [https://www.ebi.ac.uk/pdbsum/6tgd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tgd ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/M4JT39_PSEAI M4JT39_PSEAI] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Bacteria are known to evade beta-lactam antibiotic action by producing beta-lactamases (BLs), including carbapenemases, which are able to hydrolyze nearly all available beta-lactams. The production of BLs represents one of the best known and most targeted mechanisms of resistance in bacteria. We have performed the parallel screening of commercially available compounds against a panel of clinically relevant BLs: class A CTX-M-15 and KPC-2, subclass B1 NDM-1 and VIM-2 MBLs, and the class C P. aeruginosa AmpC. The results show that all BLs prefer scaffolds having electron pair donors: KPC-2 is preferentially inhibited by sulfonamide and tetrazole-based derivatives, NDM-1 by compounds bearing a thiol, a thiosemicarbazide or thiosemicarbazone moiety, while VIM-2 by triazole-containing molecules. Few broad-spectrum BLs inhibitors were identified; among these, compound 40 potentiates imipenem activity against an NDM-1-producing E. coli clinical strain. The binary complexes of the two most promising compounds binding NDM-1 and VIM-2 were obtained at high resolution, providing strong insights to improve molecular docking simulations, especially regarding the interaction of MBLs with inhibitors. | |||
Virtual screening identifies broad-spectrum beta-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases.,Spyrakis F, Santucci M, Maso L, Cross S, Gianquinto E, Sannio F, Verdirosa F, De Luca F, Docquier JD, Cendron L, Tondi D, Venturelli A, Cruciani G, Costi MP Sci Rep. 2020 Jul 29;10(1):12763. doi: 10.1038/s41598-020-69431-y. PMID:32728062<ref>PMID:32728062</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tgd" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Pseudomonas aeruginosa]] | |||
[[Category: Cendron L]] | [[Category: Cendron L]] | ||
[[Category: Costi MP]] | [[Category: Costi MP]] | ||
Latest revision as of 16:01, 24 January 2024
Crystal structure of NDM-1 in complex with triazole-based inhibitor OP31Crystal structure of NDM-1 in complex with triazole-based inhibitor OP31
Structural highlights
FunctionPublication Abstract from PubMedBacteria are known to evade beta-lactam antibiotic action by producing beta-lactamases (BLs), including carbapenemases, which are able to hydrolyze nearly all available beta-lactams. The production of BLs represents one of the best known and most targeted mechanisms of resistance in bacteria. We have performed the parallel screening of commercially available compounds against a panel of clinically relevant BLs: class A CTX-M-15 and KPC-2, subclass B1 NDM-1 and VIM-2 MBLs, and the class C P. aeruginosa AmpC. The results show that all BLs prefer scaffolds having electron pair donors: KPC-2 is preferentially inhibited by sulfonamide and tetrazole-based derivatives, NDM-1 by compounds bearing a thiol, a thiosemicarbazide or thiosemicarbazone moiety, while VIM-2 by triazole-containing molecules. Few broad-spectrum BLs inhibitors were identified; among these, compound 40 potentiates imipenem activity against an NDM-1-producing E. coli clinical strain. The binary complexes of the two most promising compounds binding NDM-1 and VIM-2 were obtained at high resolution, providing strong insights to improve molecular docking simulations, especially regarding the interaction of MBLs with inhibitors. Virtual screening identifies broad-spectrum beta-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases.,Spyrakis F, Santucci M, Maso L, Cross S, Gianquinto E, Sannio F, Verdirosa F, De Luca F, Docquier JD, Cendron L, Tondi D, Venturelli A, Cruciani G, Costi MP Sci Rep. 2020 Jul 29;10(1):12763. doi: 10.1038/s41598-020-69431-y. PMID:32728062[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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