View source for 6zyo


==Structure of VIM-2 with 2-Mercaptomethyl-thiazolidine D-syn-1b==
<StructureSection load='6zyo' size='340' side='right'caption='[[6zyo]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6zyo]] is a 2 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=6ZYO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZYO 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]] 1.45&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=QST:(2~{S},4~{S})-2-ethoxycarbonyl-5,5-dimethyl-2-(sulfanylmethyl)-1,3-thiazolidine-4-carboxylic+acid'>QST</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=6zyo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zyo OCA], [https://pdbe.org/6zyo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zyo RCSB], [https://www.ebi.ac.uk/pdbsum/6zyo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zyo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q9K2N0_PSEAI Q9K2N0_PSEAI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-beta-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all beta-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., K i = 0.44 muM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether-pi interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur-pi interactions can be exploited for general ligand design in medicinal chemistry.

2-Mercaptomethyl-thiazolidines use conserved aromatic-S interactions to achieve broad-range inhibition of metallo-beta-lactamases.,Rossi MA, Martinez V, Hinchliffe P, Mojica MF, Castillo V, Moreno DM, Smith R, Spellberg B, Drusano GL, Banchio C, Bonomo RA, Spencer J, Vila AJ, Mahler G Chem Sci. 2021 Jan 5;12(8):2898-2908. doi: 10.1039/d0sc05172a. PMID:34164056<ref>PMID:34164056</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6zyo" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Pseudomonas aeruginosa]]
[[Category: Hinchliffe P]]
[[Category: Spencer J]]