View source for 7yh9


==Crystal structure of IMP-1 MBL in complex with 3-(4-benzyl-1H-1,2,3-triazol-1-yl)phthalic acid==
<StructureSection load='7yh9' size='340' side='right'caption='[[7yh9]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7yh9]] is a 6 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=7YH9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7YH9 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]] 2.39&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IT0:3-[4-(phenylmethyl)-1,2,3-triazol-1-yl]phthalic+acid'>IT0</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=7yh9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7yh9 OCA], [https://pdbe.org/7yh9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7yh9 RCSB], [https://www.ebi.ac.uk/pdbsum/7yh9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7yh9 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q79MP6_PSEAI Q79MP6_PSEAI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The emergence of metallo-beta-lactamases (MBLs) confers resistance to nearly all the beta-lactam antibiotics, including carbapenems. Currently, there is a lack of clinically useful MBL inhibitors, making it crucial to discover new inhibitor chemotypes that can potently target multiple clinically relevant MBLs. Herein we report a strategy that utilizes a metal binding pharmacophore (MBP) click approach to identify new broad-spectrum MBL inhibitors. Our initial investigation identified several MBPs including phthalic acid, phenylboronic acid and benzyl phosphoric acid, which were subjected to structural transformations using azide-alkyne click reactions. Subsequent structure-activity relationship analyses led to the identification of several potent broad-spectrum MBL inhibitors, including 73 that manifested IC(50) values ranging from 0.00012 muM to 0.64 muM against multiple MBLs. Co-crystallographic studies demonstrated the importance of MBPs in engaging with the MBL active site anchor pharmacophore features, and revealed the unusual two-molecule binding modes with IMP-1, highlighting the critical role of flexible active site loops in recognizing structurally diverse substrates/inhibitors. Our work provides new chemotypes for MBL inhibition and establishes a MBP click-derived paradigm for inhibitor discovery targeting MBLs as well as other metalloenzymes.

Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-beta-lactamase inhibitors.,Yan YH, Ding HS, Zhu KR, Mu BS, Zheng Y, Huang MY, Zhou C, Li WF, Wang Z, Wu Y, Li GB Eur J Med Chem. 2023 May 13;257:115473. doi: 10.1016/j.ejmech.2023.115473. PMID:37209449<ref>PMID:37209449</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7yh9" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Pseudomonas aeruginosa]]
[[Category: Li G-B]]
[[Category: Yan Y-H]]