4pvt
Crystal Structure of VIM-2 metallo-beta-lactamase in complex with ML302FCrystal Structure of VIM-2 metallo-beta-lactamase in complex with ML302F
Structural highlights
FunctionPublication Abstract from PubMedThe use of beta-lactam antibiotics is compromised by resistance, which is provided by beta-lactamases belonging to both metallo (MBL)- and serine (SBL)-beta-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 beta-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. Rhodanine hydrolysis leads to potent thioenolate mediated metallo-beta-lactamase inhibition.,Brem J, van Berkel SS, Aik W, Rydzik AM, Avison MB, Pettinati I, Umland KD, Kawamura A, Spencer J, Claridge TD, McDonough MA, Schofield CJ Nat Chem. 2014 Dec;6(12):1084-90. doi: 10.1038/nchem.2110. Epub 2014 Nov 17. PMID:25411887[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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