5nde
Crystal structure of metallo-beta-lactamase SPM-1 in space group P4222Crystal structure of metallo-beta-lactamase SPM-1 in space group P4222
Structural highlights
Publication Abstract from PubMedThe most important resistance mechanism to beta-lactam antibiotics involves hydrolysis by two beta-lactamase categories: the nucleophilic serine (SBL) and the metallo- (MBL) beta-lactamases. Cyclobutanones are hydrolytically stable beta-lactam analogues with potential to inhibit both SBLs and MBLs. We describe solution and crystallographic studies on the interaction of a cyclobutanone penem analogue with the clinically important MBL SPM-1. NMR experiments using 19F-labeled SPM-1 imply the cyclobutanone binds to SPM-1 with micromolar affinity. A crystal structure of the SPM-1:cyclobutanone complex reveals binding of the hydrated cyclobutanone via interactions with one of the zinc ions, stabilisation of the hydrate by hydrogen bonding to zinc-bound water, and hydrophobic contacts with aromatic residues. NMR analyses using a 13C-labeled cyclobutanone support assignment of the bound species as the hydrated ketone. The results inform on how MBLs bind substrates and stabilize tetrahedral intermediates. They support further investigations on the use of transition state and/or intermediate analogues as inhibitors of all beta-lactamase classes. Cyclobutanone Mimics of Intermediates in Metallo-beta-Lactamase Catalysis.,Abboud MI, Kosmopoulou M, Krismanich A, Johnson JW, Hinchliffe P, Brem J, Claridge TDW, Spencer J, Schofield C, Dmitrienko GI Chemistry. 2017 Dec 17. doi: 10.1002/chem.201705886. PMID:29250863[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||