8QNZ

Crystal Structure of a Class D Carbapenemase Complexed with Hydrolyzed Imipenem

これはPDB形式変換不可エントリーです。

8QNZ の概要

• エントリーDOI: 10.2210/pdb8qnz/pdb
• 分子名称: Beta-lactamase, (2R)-2-[(2S,3R)-1,3-bis(oxidanyl)-1-oxidanylidene-butan-2-yl]-4-(2-methanimidamidoethylsulfanyl)-2,3-dihydro-1H-pyrrole -5-carboxylic acid, BROMIDE ION, ... (5 entities in total)
• 機能のキーワード: oxa, imipenem, hydrolase
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 122921.68

構造登録者

Zhou, Q.,He, Y.,Jin, Y. (登録日: 2023-09-27, 公開日: 2023-11-08, 最終更新日: 2024-03-13)

主引用文献

Zhou, Q.,Catalan, P.,Bell, H.,Baumann, P.,Cooke, R.,Evans, R.,Yang, J.,Zhang, Z.,Zappala, D.,Zhang, Y.,Blackburn, G.M.,He, Y.,Jin, Y.
An Ion-Pair Induced Intermediate Complex Captured in Class D Carbapenemase Reveals Chloride Ion as a Janus Effector Modulating Activity.
Acs Cent.Sci., 9:2339-2349, 2023

PubMed Abstract: Antibiotic-resistant that produce oxacillinase (OXA)-48-like Class D β-lactamases are often linked to increased clinical mortality. Though the catalytic mechanism of OXA-48 is known, the molecular origin of its biphasic kinetics has been elusive. We here identify selective chloride binding rather than decarbamylation of the carbamylated lysine as the source of biphasic kinetics, utilizing isothermal titration calorimetry (ITC) to monitor the complete reaction course with the OXA-48 variant having a chemically stable -acetyl lysine. Further structural investigation enables us to capture an unprecedented inactive acyl intermediate wedged in place by a halide ion paired with a conserved active site arginine. Supported by mutagenesis and mathematical simulation, we identify chloride as a "Janus effector" that operates by allosteric activation of the burst phase and by inhibition of the steady state in kinetic assays of β-lactams. We show that chloride-induced biphasic kinetics directly affects antibiotic efficacy and facilitates the differentiation of clinical isolates encoding Class D from Class A and B carbapenemases. As chloride is present in laboratory and clinical procedures, our discovery greatly expands the roles of chloride in modulating enzyme catalysis and highlights its potential impact on the pharmacokinetics and efficacy of antibiotics during treatment.

PubMed: 38161376
DOI: 10.1021/acscentsci.3c00609

実験手法

X-RAY DIFFRACTION (1.53 Å)