5TW8

Crystal structure of wild-type S. aureus penicillin binding protein 4 (PBP4) in complex with ceftaroline

5TW8 の概要

• エントリーDOI: 10.2210/pdb5tw8/pdb
• 関連するPDBエントリー: 5TW4
• 分子名称: Penicillin-binding protein 4, Ceftaroline, bound form, ZINC ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, penicillin binding protein, beta-lactam antibiotics, hydrolase - antibiotic complex, hydrolase / antibiotic
• 由来する生物種: Staphylococcus aureus (strain COL)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82002.91

構造登録者

Alexander, J.A.N.,Strynadka, N.C.J. (登録日: 2016-11-11, 公開日: 2018-05-16, 最終更新日: 2024-10-30)

主引用文献

Alexander, J.A.N.,Chatterjee, S.S.,Hamilton, S.M.,Eltis, L.D.,Chambers, H.F.,Strynadka, N.C.J.
Structural and kinetic analysis of penicillin-binding protein 4 (PBP4)-mediated antibiotic resistance inStaphylococcus aureus.
J. Biol. Chem., 2018

PubMed Abstract: Methicillin-resistant (MRSA) causes serious community-acquired and nosocomial infections worldwide. MRSA strains are resistant to a variety of antibiotics, including the classic penicillin and cephalosporin classes of β-lactams, making them intractable to treatment. Although β-lactam resistance in MRSA has been ascribed to the acquisition and activity of penicillin-binding protein 2a (PBP2a, encoded by ), it has recently been observed that resistance can also be mediated by penicillin-binding protein 4 (PBP4). Previously, we have shown that broad-spectrum β-lactam resistance can arise following serial passaging of a -negative COL strain of creating the CRB strain. This strain has two missense mutations in and a mutation in the promoter, both of which play an instrumental role in β-lactam resistance. To better understand PBP4's role in resistance, here we have characterized its kinetics and structure with clinically relevant β-lactam antibiotics. We present the first crystallographic PBP4 structures of apo and acyl-enzyme intermediate forms complexed with three late-generation β-lactam antibiotics: ceftobiprole, ceftaroline, and nafcillin. In parallel, we characterized the structural and kinetic effects of the PBP4 mutations present in the CRB strain. Localized within the transpeptidase active-site cleft, the two substitutions appear to have different effects depending on the drug. With ceftobiprole, the missense mutations impaired the value 150-fold, decreasing the proportion of inhibited PBP4. However, ceftaroline resistance appeared to be mediated by other factors, possibly including mutation of the promoter. Our findings provide evidence that CRB has at least two PBP4-mediated resistance mechanisms.

PubMed: 30366985
DOI: 10.1074/jbc.RA118.004952

実験手法

X-RAY DIFFRACTION (1.72 Å)