View source for 6zys


==Structure of IMP-1 with 2-Mercaptomethyl-thiazolidine D-syn-1b==
<StructureSection load='6zys' size='340' side='right'caption='[[6zys]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6zys]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Serratia_marcescens Serratia marcescens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZYS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZYS 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]] 1.8700095&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=6zys FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zys OCA], [https://pdbe.org/6zys PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zys RCSB], [https://www.ebi.ac.uk/pdbsum/6zys PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zys ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/BLAB_SERMA BLAB_SERMA] Confers resistance to imipenem and broad-spectrum beta-lactams. Also hydrolyzes carbapenems.
<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 6zys" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Serratia marcescens]]
[[Category: Hinchliffe P]]
[[Category: Spencer J]]