6ew3: Difference between revisions
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==Crystal structure of the metallo-beta-lactamase VIM-2 with ML302F== | |||
<StructureSection load='6ew3' size='340' side='right' caption='[[6ew3]], [[Resolution|resolution]] 2.14Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ew3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EW3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EW3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=S3C:(2Z)-2-SULFANYL-3-(2,3,6-TRICHLOROPHENYL)PROP-2-ENOIC+ACID'>S3C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pvo|4pvo]]</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ew3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ew3 OCA], [http://pdbe.org/6ew3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ew3 RCSB], [http://www.ebi.ac.uk/pdbsum/6ew3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ew3 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Metallo-beta-lactamases (MBLs) enable bacterial resistance to almost all classes of beta-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products. | |||
Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-beta-lactamases.,Zhang D, Markoulides MS, Stepanovs D, Rydzik AM, El-Hussein A, Bon C, Kamps JJAG, Umland KD, Collins PM, Cahill ST, Wang DY, von Delft F, Brem J, McDonough MA, Schofield CJ Bioorg Med Chem. 2018 Jul 15;26(11):2928-2936. doi: 10.1016/j.bmc.2018.02.043., Epub 2018 Feb 23. PMID:29655609<ref>PMID:29655609</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ew3" style="background-color:#fffaf0;"></div> | |||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Berkel, S S.van]] | |||
[[Category: Brem, J]] | [[Category: Brem, J]] | ||
[[Category: | [[Category: Collins, P M]] | ||
[[Category: Schofield, C | [[Category: Delft, F von]] | ||
[[Category: | [[Category: McDonough, M A]] | ||
[[Category: Schofield, C J]] | |||
[[Category: Antibiotic resistance]] | |||
[[Category: Complex]] | |||
[[Category: Hydrolase]] | |||
[[Category: Metal binding]] | |||
[[Category: Xchem]] | |||
Latest revision as of 10:49, 3 October 2018
Crystal structure of the metallo-beta-lactamase VIM-2 with ML302FCrystal structure of the metallo-beta-lactamase VIM-2 with ML302F
Structural highlights
Publication Abstract from PubMedMetallo-beta-lactamases (MBLs) enable bacterial resistance to almost all classes of beta-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products. Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-beta-lactamases.,Zhang D, Markoulides MS, Stepanovs D, Rydzik AM, El-Hussein A, Bon C, Kamps JJAG, Umland KD, Collins PM, Cahill ST, Wang DY, von Delft F, Brem J, McDonough MA, Schofield CJ Bioorg Med Chem. 2018 Jul 15;26(11):2928-2936. doi: 10.1016/j.bmc.2018.02.043., Epub 2018 Feb 23. PMID:29655609[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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