OCA at 13:34, 24 January 2024

OCA — Wed, 24 Jan 2024 13:34:09 GMT

←Older revision		Revision as of 13:34, 24 January 2024
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	==Crystal Structure of the VIM-2 Acquired Metallo-beta-Lactamase in Complex with JMV-4690 (Cpd 31)==		==Crystal Structure of the VIM-2 Acquired Metallo-beta-Lactamase in Complex with JMV-4690 (Cpd 31)==
-	<StructureSection load='6yrp' size='340' side='right'caption='[[6yrp]]' scene=''>	+	<StructureSection load='6yrp' size='340' side='right'caption='[[6yrp]], [[Resolution\|resolution]] 1.95Å' 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=6YRP OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6YRP FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6yrp]] 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=6YRP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YRP FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6yrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yrp OCA], [~~http~~://pdbe.org/6yrp PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6yrp RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6yrp PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6yrp ProSAT]</span></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.95Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PJB:2-[[[3-(5-methoxy-2-oxidanyl-phenyl)-5-sulfanylidene-1~{H}-1,2,4-triazol-4-yl]amino]methyl]benzoic+acid'>PJB</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=6yrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yrp OCA], [https://pdbe.org/6yrp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yrp RCSB], [https://www.ebi.ac.uk/pdbsum/6yrp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yrp ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/B8QIQ9_PSEAI B8QIQ9_PSEAI]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Resistance to beta-lactam antibiotics in Gram-negatives producing metallo-beta-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the muM to sub-muM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several beta-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.
		+
		+	4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-beta-lactamase inhibitors.,Gavara L, Sevaille L, De Luca F, Mercuri P, Bebrone C, Feller G, Legru A, Cerboni G, Tanfoni S, Baud D, Cutolo G, Bestgen B, Chelini G, Verdirosa F, Sannio F, Pozzi C, Benvenuti M, Kwapien K, Fischer M, Becker K, Frere JM, Mangani S, Gresh N, Berthomieu D, Galleni M, Docquier JD, Hernandez JF Eur J Med Chem. 2020 Aug 20;208:112720. doi: 10.1016/j.ejmech.2020.112720. PMID:32937203<ref>PMID:32937203</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6yrp" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
		+	[[Category: Pseudomonas aeruginosa]]
	[[Category: Benvenuti M]]		[[Category: Benvenuti M]]
	[[Category: De Luca F]]		[[Category: De Luca F]]

OCA at 07:11, 30 September 2020

OCA — Wed, 30 Sep 2020 07:11:30 GMT

←Older revision		Revision as of 07:11, 30 September 2020
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-	'''Unreleased structure'''

-	~~The entry~~ 6yrp is ~~ON HOLD until Paper Publication~~	+	==Crystal Structure of the VIM-2 Acquired Metallo-beta-Lactamase in Complex with JMV-4690 (Cpd 31)==
-		+	<StructureSection load='6yrp' size='340' side='right'caption='[[6yrp]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YRP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YRP FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6yrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yrp OCA], [http://pdbe.org/6yrp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yrp RCSB], [http://www.ebi.ac.uk/pdbsum/6yrp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yrp ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Benvenuti M]]
		+	[[Category: De Luca F]]
		+	[[Category: Docquier JD]]
		+	[[Category: Mangani S]]
		+	[[Category: Pozzi C]]

OCA at 07:33, 22 July 2020

OCA — Wed, 22 Jul 2020 07:33:03 GMT

←Older revision		Revision as of 07:33, 22 July 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6yrp is ON HOLD	+	The entry 6yrp is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6yrp" [edit=sysop:move=sysop]

OCA — Wed, 29 Apr 2020 05:27:41 GMT

Protected "6yrp" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:27, 29 April 2020

OCA: New page: '''Unreleased structure''' The entry 6yrp is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 29 Apr 2020 05:27:40 GMT

New page: '''Unreleased structure''' The entry 6yrp is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6yrp is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

6yrp - Revision history

OCA at 13:34, 24 January 2024

OCA at 07:11, 30 September 2020

OCA at 07:33, 22 July 2020

OCA: Protected "6yrp" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6yrp is ON HOLD Authors: Description: Category: Unreleased Structures