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Crystal structures of penicillin-binding protein 3 in complex with azlocillin and cefoperazone in both acylated and deacylated forms

DOI: 10.1002/1873-3468.12054 DOI Help
PMID: 26823174 PMID Help

Authors: Jingshan Ren (University of Oxford) , Joanne E. Nettleship (University of Oxford) , Alexandra Males (University of Oxford) , Dave Stuart (Diamond Light Source; University of Oxford) , Ray Owens (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Febs Letters

State: Published (Approved)
Published: January 2016

Abstract: Penicillin-binding protein 3 (PBP3) from Pseudomonas aeruginosa is themolecular target of b-lactam-based antibiotics. Structures of PBP3 in com-plexes with azlocillin and cefoperazone, which are in clinical use for the treat-ment of pseudomonad infections, have been determined to 2.0A resolution.Together with data from other complexes, these structures identify a commonset of residues involved in the binding of b-lactams to PBP3. Comparison ofwild-type and an active site mutant (S294A) showed that increased thermalstability of PBP3 following azlocillin binding was entirely due to covalentbinding to S294, whereas cefoperazone binding produces some increase in sta-bility without the covalent link. Consistent with this, a third crystal structurewas determined in which the hydrolysis product of cefoperazone was noncova-lently bound in the active site of PBP3. This is the first structure of a com-plex between a penicillin-binding protein and cephalosporic acid and may beimportant in the design of new noncovalent PBP3 inhibitors.

Journal Keywords: azlocillin; cefoperazone; penicillin-binding protein; Pseudomonasaeruginosa; ther mal shift assay; b-lactam antibiotics

Subject Areas: Medicine

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/01/2016 16:29

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