5MOZ

OXA-10 Avibactam complex with bound Iodide

5MOZ の概要

• エントリーDOI: 10.2210/pdb5moz/pdb
• 分子名称: Beta-lactamase OXA-10, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, GLYCEROL, ... (7 entities in total)
• 機能のキーワード: antibiotic resisitance, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57586.69

構造登録者

Brem, J. (登録日: 2016-12-15, 公開日: 2017-07-12, 最終更新日: 2024-10-09)

主引用文献

Lohans, C.T.,Wang, D.Y.,Jorgensen, C.,Cahill, S.T.,Clifton, I.J.,McDonough, M.A.,Oswin, H.P.,Spencer, J.,Domene, C.,Claridge, T.D.W.,Brem, J.,Schofield, C.J.
(13)C-Carbamylation as a mechanistic probe for the inhibition of class D beta-lactamases by avibactam and halide ions.
Org. Biomol. Chem., 15:6024-6032, 2017

PubMed Abstract: The class D (OXA) serine β-lactamases are a major cause of resistance to β-lactam antibiotics. The class D enzymes are unique amongst β-lactamases because they have a carbamylated lysine that acts as a general acid/base in catalysis. Previous crystallographic studies led to the proposal that β-lactamase inhibitor avibactam targets OXA enzymes in part by promoting decarbamylation. Similarly, halide ions are proposed to inhibit OXA enzymes via decarbamylation. NMR analyses, in which the carbamylated lysines of OXA-10, -23 and -48 were C-labelled, indicate that reaction with avibactam does not ablate lysine carbamylation in solution. While halide ions did not decarbamylate the C-labelled OXA enzymes in the absence of substrate or inhibitor, avibactam-treated OXA enzymes were susceptible to decarbamylation mediated by halide ions, suggesting halide ions may inhibit OXA enzymes by promoting decarbamylation of acyl-enzyme complex. Crystal structures of the OXA-10 avibactam complex were obtained with bromide, iodide, and sodium ions bound between Trp-154 and Lys-70. Structures were also obtained wherein bromide and iodide ions occupy the position expected for the 'hydrolytic water' molecule. In contrast with some solution studies, Lys-70 was decarbamylated in these structures. These results reveal clear differences between crystallographic and solution studies on the interaction of class D β-lactamases with avibactam and halides, and demonstrate the utility of C-NMR for studying lysine carbamylation in solution.

PubMed: 28678295
DOI: 10.1039/c7ob01514c

実験手法

X-RAY DIFFRACTION (1.34 Å)