7yhc: Difference between revisions
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==Crystal structure of VIM-2 MBL in complex with 3-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)phthalic acid== | |||
<StructureSection load='7yhc' size='340' side='right'caption='[[7yhc]], [[Resolution|resolution]] 2.15Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7yhc]] is a 8 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=7YHC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7YHC 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]] 2.153Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IU3:3-[4-(3-aminophenyl)-1,2,3-triazol-1-yl]phthalic+acid'>IU3</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=7yhc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7yhc OCA], [https://pdbe.org/7yhc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7yhc RCSB], [https://www.ebi.ac.uk/pdbsum/7yhc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7yhc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9K2N0_PSEAI Q9K2N0_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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7yhc" style="background-color:#fffaf0;"></div> | ||
[[Category: Li | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Pseudomonas aeruginosa]] | |||
[[Category: Li G-B]] | |||
[[Category: Yan Y-H]] | |||
Latest revision as of 21:09, 29 November 2023
Crystal structure of VIM-2 MBL in complex with 3-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)phthalic acidCrystal structure of VIM-2 MBL in complex with 3-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)phthalic acid
Structural highlights
FunctionPublication Abstract from PubMedThe 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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