4PVT

Crystal Structure of VIM-2 metallo-beta-lactamase in complex with ML302F

Summary for 4PVT

• Entry DOI: 10.2210/pdb4pvt/pdb
• Related: 1KO2 1KO3 4PVO
• Descriptor: Beta-lactamase class B VIM-2, ZINC ION, (2Z)-2-sulfanyl-3-(2,3,6-trichlorophenyl)prop-2-enoic acid, ... (6 entities in total)
• Functional Keywords: alpha-beta/beta-alpha, beta-lactamase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 52622.74

Authors

Aik, W.S.,Brem, J.,McDonough, M.A.,Schofield, C.J. (deposition date: 2014-03-18, release date: 2014-11-19, Last modification date: 2023-11-08)

Primary citation

Brem, J.,van Berkel, S.S.,Aik, W.,Rydzik, A.M.,Avison, M.B.,Pettinati, I.,Umland, K.D.,Kawamura, A.,Spencer, J.,Claridge, T.D.,McDonough, M.A.,Schofield, C.J.
Rhodanine hydrolysis leads to potent thioenolate mediated metallo-beta-lactamase inhibition.
Nat.Chem., 6:1084-1090, 2014

PubMed Abstract: The use of β-lactam antibiotics is compromised by resistance, which is provided by β-lactamases belonging to both metallo (MBL)- and serine (SBL)-β-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in β-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including (19)F NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.

PubMed: 25411887
DOI: 10.1038/nchem.2110

Experimental method

X-RAY DIFFRACTION (2 Å)