5WI3

Structure of Acinetobacter baumannii carbapenemase OXA-239 K82D bound to cefotaxime

5WI3 の概要

• エントリーDOI: 10.2210/pdb5wi3/pdb
• 分子名称: OXA-239, CEFOTAXIME, C3' cleaved, open, bound form (3 entities in total)
• 機能のキーワード: beta-lactamase, antibiotic resistance, hydrolase
• 由来する生物種: Acinetobacter sp. enrichment culture clone 8407
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 58367.19

構造登録者

Harper, T.M.,June, C.M.,Powers, R.A.,Leonard, D.A. (登録日: 2017-07-18, 公開日: 2017-12-27, 最終更新日: 2024-10-23)

主引用文献

Harper, T.M.,June, C.M.,Taracila, M.A.,Bonomo, R.A.,Powers, R.A.,Leonard, D.A.
Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239.
Biochem. J., 475:273-288, 2018

PubMed Abstract: OXA-239 is a class D carbapenemase isolated from an strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced ∼3-fold and 20-fold, respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical with that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of β-lactam drugs.

PubMed: 29229762
DOI: 10.1042/BCJ20170702

実験手法

X-RAY DIFFRACTION (1.81 Å)