View source for 7dux


==Crystal structure of VIM-2 MBL in complex with 1-(but-3-en-1-yl)-1H-imidazole-2-carboxylic acid==
<StructureSection load='7dux' size='340' side='right'caption='[[7dux]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7dux]] is a 1 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=7DUX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DUX 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]] 1.981&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HLF:1-but-3-enylimidazole-2-carboxylic+acid'>HLF</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=7dux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dux OCA], [https://pdbe.org/7dux PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dux RCSB], [https://www.ebi.ac.uk/pdbsum/7dux PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dux ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q9K2N0_PSEAI Q9K2N0_PSEAI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Production of metallo-beta-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the 'last-resort' carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.

Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-beta-lactamase inhibitors.,Yan YH, Li W, Chen W, Li C, Zhu KR, Deng J, Dai QQ, Yang LL, Wang Z, Li GB Eur J Med Chem. 2022 Jan 15;228:113965. doi: 10.1016/j.ejmech.2021.113965. Epub, 2021 Nov 2. PMID:34763944<ref>PMID:34763944</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7dux" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Pseudomonas aeruginosa]]
[[Category: Li G-B]]
[[Category: Yan Y-H]]