View source for 5dpx


==1,2,4-Triazole-3-thione compounds as inhibitors of L1, di-zinc metallo-beta-lactamases.==
<StructureSection load='5dpx' size='340' side='right'caption='[[5dpx]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5dpx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Stenotrophomonas_maltophilia Stenotrophomonas maltophilia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DPX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DPX 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]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L3B:5-(2-METHYLPHENYL)-3H-1,2,4-TRIAZOLE-3-THIONE'>L3B</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5dpx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dpx OCA], [https://pdbe.org/5dpx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dpx RCSB], [https://www.ebi.ac.uk/pdbsum/5dpx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dpx ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/BLA1_STEMA BLA1_STEMA] Has a high activity against imipenem.
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== Publication Abstract from PubMed ==
Metallo-beta-lactamases (MBL) cause resistance of Gram-negative bacteria to beta-lactam antibiotics and are of serious concern because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We have previously identified the original binding mode of a 4-amino-1,2,4-triazole-3-thione compound, IIIA, within the di-zinc active site of the L1 MBL. Here, we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB. Unexpectedly, IIIB showed a similar but reverse binding mode compared to IIIA. These 3D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of di-zinc metallo-enzymes. Based on these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the muM range towards at least one of five representative MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2 and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial di-nuclear Zn-dependent hydrolases belonging to the MBL fold superfamily (i.e. endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. While the bacterial tRNases were not inhibited, the best IC50's towards plasmodial glyoxalase II were in the 10 muM range.

1,2,4-Triazole-3-thione compounds as inhibitors of di-zinc metallo-beta-lactamases.,Sevaille L, Gavara L, Bebrone C, De Luca F, Nauton L, Achard M, Mercuri P, Tanfoni S, Borgianni L, Guyon C, Lonjon P, Turan-Zitouni G, Dzieciolowski J, Becker K, Benard L, Condon C, Maillard L, Martinez J, Frere JM, Dideberg O, Galleni M, Docquier JD, Hernandez JF ChemMedChem. 2017 May 15. doi: 10.1002/cmdc.201700186. PMID:28505394<ref>PMID:28505394</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5dpx" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Stenotrophomonas maltophilia]]
[[Category: Dideberg O]]
[[Category: Garau G]]
[[Category: Khan R]]
[[Category: Nauton L]]