9H18

Crystal structure of OXA-405 in complex with nacubactam

これはPDB形式変換不可エントリーです。

9H18 の概要

• エントリーDOI: 10.2210/pdb9h18/pdb
• 分子名称: Beta-lactamase, (2S,5R)-N-(2-aminoethoxy)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, DI(HYDROXYETHYL)ETHER, ... (8 entities in total)
• 機能のキーワード: antibiotic resistance, beta lactamase, class d, dbo, antimicrobial protein
• 由来する生物種: Serratia marcescens
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57509.31

構造登録者

Hoff, J.F.,Goudar, K.E.,Hinchliffe, P.,Spencer, J. (登録日: 2024-10-09, 公開日: 2025-09-03, 最終更新日: 2025-11-26)

主引用文献

Hoff, J.F.,Goudar, K.E.,Calvopina, K.,Beer, M.,Hinchliffe, P.,Shaw, J.M.,Tooke, C.L.,Takebayashi, Y.,Cadzow, A.F.,Harmer, N.J.,Mulholland, A.J.,Schofield, C.J.,Spencer, J.
Electrostatic interactions influence diazabicyclooctane inhibitor potency against OXA-48-like beta-lactamases.
Rsc Med Chem, 16:5441-5455, 2025

PubMed Abstract: Carbapenemases, β-lactamases hydrolysing carbapenem antibiotics, challenge the treatment of multi-drug resistant bacteria. The OXA-48 carbapenemase is widely disseminated in , necessitating new treatments for producer strains. Diazabicyclooctane (DBO) inhibitors, including avibactam and nacubactam, act on a wide range of enzymes to overcome β-lactamase-mediated resistance. Here we describe investigations on how avibactam and nacubactam inhibit OXA-48 and two variants, OXA-163 and OXA-405, with deletions in the β5-β6 loop neighbouring the active site that modify activity towards different β-lactam classes. Nacubactam is ∼80-fold less potent than avibactam towards OXA-48, but this difference reduces in OXA-163 and OXA-405. Crystal structures and molecular dynamics simulations reveal electrostatic repulsion between Arg214 on the OXA-48 β5-β6 active-site loop and nacubactam, but not avibactam; effects absent from simulations of OXA-163 and OXA-405, which lack Arg214. Crystallographic and mass spectrometry data demonstrate that all three enzymes support desulfation of the bound DBOs. The results indicate that interactions with Arg214 affect DBO potency, suggesting that sequence variation in OXA-48-like β-lactamases affects reactivity towards inhibitors as well as β-lactam substrates.

PubMed: 40927637
DOI: 10.1039/d5md00512d

実験手法

X-RAY DIFFRACTION (1.33 Å)