6HOO

Crystal Structure of Rationally Designed OXA-48loop18 beta-lactamase

6HOO の概要

• エントリーDOI: 10.2210/pdb6hoo/pdb
• 分子名称: Beta-lactamase,OXA-48loop18,Beta-lactamase, SULFATE ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: class d beta-lactamase oxa-48loop18, antibiotic, hydrolase
• 由来する生物種: Klebsiella pneumoniae; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59415.66

構造登録者

Zavala, A.,Retailleau, P.,Dabos, L.,Naas, T.,Iorga, B. (登録日: 2018-09-17, 公開日: 2019-10-09, 最終更新日: 2024-01-24)

主引用文献

Dabos, L.,Zavala, A.,Bonnin, R.A.,Beckstein, O.,Retailleau, P.,Iorga, B.I.,Naas, T.
Substrate Specificity of OXA-48 after beta 5-beta 6 Loop Replacement.
Acs Infect Dis., 6:1032-1043, 2020

PubMed Abstract: OXA-48 carbapenemase has rapidly spread in many countries worldwide with several OXA-48-variants being described, differing by a few amino acid (AA) substitutions or deletions, mostly in the β5-β6 loop. While single AA substitutions have only a minor impact on OXA-48 hydrolytic profiles, others with 4 AA deletions result in loss of carbapenem hydrolysis and gain of expanded-spectrum cephalosporin (ESC) hydrolysis. We have replaced the β5-β6 loop of OXA-48 with that of OXA-18, a clavulanic-acid inhibited oxacillinase capable of hydrolyzing ESCs but not carbapenems. The hybrid enzyme OXA-48Loop18 was able to hydrolyze ESCs and carbapenems (although with a lower ), even though the β5-β6 loop was longer and its sequence quite different from that of OXA-48. The kinetic parameters of OXA-48Loop18 were in agreement with the MIC values. X-ray crystallography and molecular modeling suggest that the conformation of the grafted loop allows the binding of bulkier substrates, unlike that of the native loop, expanding the hydrolytic profile. This seems to be due not only to differences in AA sequence, but also to the backbone conformation the loop can adopt. Finally, our results provide further experimental evidence for the role of the β5-β6 loop in substrate selectivity of OXA-48-like enzymes and additional details on the structure-function relationship of β-lactamases, demonstrating how localized changes in these proteins can alter or expand their function, highlighting their plasticity.

PubMed: 32156115
DOI: 10.1021/acsinfecdis.9b00452

実験手法

X-RAY DIFFRACTION (2.38 Å)