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Crystal structures of penicillin‐binding protein 3 in complexes with azlocillin and cefoperazone in both acylated and deacylated forms
Author(s) -
Ren Jingshan,
Nettleship Joanne E.,
Males Alexandra,
Stuart David I.,
Owens Raymond J.
Publication year - 2016
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12054
Subject(s) - azlocillin , cefoperazone , chemistry , penicillin , binding site , stereochemistry , penicillin binding proteins , pseudomonas aeruginosa , antibiotics , biochemistry , imipenem , bacteria , biology , piperacillin , antibiotic resistance , genetics
Penicillin‐binding protein 3 ( PBP 3) from Pseudomonas aeruginosa is the molecular target of β‐lactam‐based antibiotics. Structures of PBP 3 in complexes with azlocillin and cefoperazone, which are in clinical use for the treatment of pseudomonad infections, have been determined to 2.0 Å resolution. Together with data from other complexes, these structures identify a common set of residues involved in the binding of β‐lactams to PBP 3. Comparison of wild‐type and an active site mutant (S294A) showed that increased thermal stability of PBP 3 following azlocillin binding was entirely due to covalent binding to S294, whereas cefoperazone binding produces some increase in stability without the covalent link. Consistent with this, a third crystal structure was determined in which the hydrolysis product of cefoperazone was noncovalently bound in the active site of PBP 3. This is the first structure of a complex between a penicillin‐binding protein and cephalosporic acid and may be important in the design of new noncovalent PBP 3 inhibitors.