4WMC

OXA-48 covalent complex with Avibactam inhibitor

4WMC の概要

• エントリーDOI: 10.2210/pdb4wmc/pdb
• 関連するPDBエントリー: 3HBR
• 分子名称: Beta-lactamase, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, CARBON DIOXIDE, ... (5 entities in total)
• 機能のキーワード: oxa-48, class d carbapenemase, avibactam, inhibitor, hydrolase
• 由来する生物種: Klebsiella pneumoniae; 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 226794.26

構造登録者

Mangani, S.,Benvenuti, M.,Docquier, J.D. (登録日: 2014-10-08, 公開日: 2014-12-03, 最終更新日: 2024-01-10)

主引用文献

Lahiri, S.D.,Mangani, S.,Jahic, H.,Benvenuti, M.,Durand-Reville, T.F.,De Luca, F.,Ehmann, D.E.,Rossolini, G.M.,Alm, R.A.,Docquier, J.D.
Molecular Basis of Selective Inhibition and Slow Reversibility of Avibactam against Class D Carbapenemases: A Structure-Guided Study of OXA-24 and OXA-48.
Acs Chem.Biol., 10:591-600, 2015

PubMed Abstract: The Class D (or OXA-type) β-lactamases have expanded to be the most diverse group of serine β-lactamases with a highly heterogeneous β-lactam hydrolysis profile and are typically resistant to marketed β-lactamase inhibitors. Class D enzymes are increasingly found in multidrug resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and various species of the Enterobacteriaceae and are posing a serious threat to the clinical utility of β-lactams including the carbapenems, which are typically reserved as the drugs of last resort. Avibactam, a novel non-β-lactam β-lactamase inhibitor, not only inhibits all class A and class C β-lactamases but also has the promise of inhibition of certain OXA enzymes, thus extending the antibacterial activity of the β-lactam used in combination to the organisms that produce these enzymes. X-ray structures of OXA-24 and OXA-48 in complex with avibactam revealed the binding mode of this inhibitor in this diverse class of enzymes and provides a rationale for selective inhibition of OXA-48 members. Additionally, various subunits of the OXA-48 structure in the asymmetric unit provide snapshots of different states of the inhibited enzyme. Overall, these data provide the first structural evidence of the exceptionally slow reversibility observed with avibactam in class D β-lactamases. Mechanisms for acylation and deacylation of avibactam by class D enzymes are proposed, and the likely extent of inhibition of class D β-lactamases by avibactam is discussed.

PubMed: 25406838
DOI: 10.1021/cb500703p

実験手法

X-RAY DIFFRACTION (2.3 Å)