6EW3

Crystal structure of the metallo-beta-lactamase VIM-2 with ML302F

Summary for 6EW3

• Entry DOI: 10.2210/pdb6ew3/pdb
• Related: 4PVO
• Descriptor: Metallo-beta-lactamase VIM-2, ZINC ION, FORMIC ACID, ... (7 entities in total)
• Functional Keywords: metal binding, hydrolase, antibiotic resistance, xchem, complex
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 51024.69

Authors

Collins, P.M.,Brem, J.,McDonough, M.A.,van Berkel, S.S.,von Delft, F.,Schofield, C.J. (deposition date: 2017-11-03, release date: 2018-10-03, Last modification date: 2024-01-17)

Primary citation

Zhang, D.,Markoulides, M.S.,Stepanovs, D.,Rydzik, A.M.,El-Hussein, A.,Bon, C.,Kamps, J.J.A.G.,Umland, K.D.,Collins, P.M.,Cahill, S.T.,Wang, D.Y.,von Delft, F.,Brem, J.,McDonough, M.A.,Schofield, C.J.
Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-beta-lactamases.
Bioorg. Med. Chem., 26:2928-2936, 2018

PubMed Abstract: Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-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.

PubMed: 29655609
DOI: 10.1016/j.bmc.2018.02.043

Experimental method

X-RAY DIFFRACTION (2.14 Å)