5FQA

Crystal Structure of Bacillus cereus Metallo-Beta-Lactamase II

5FQA の概要

• エントリーDOI: 10.2210/pdb5fqa/pdb
• 関連するPDBエントリー: 4C09
• 分子名称: BETA-LACTAMASE 2, FE (III) ION, GLYCEROL, ... (7 entities in total)
• 機能のキーワード: hydrolase, antibiotic resistance, lactamase
• 由来する生物種: BACILLUS CEREUS
• 細胞内の位置: Periplasm : P04190
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25406.45

構造登録者

Cahill, S.T.,Brem, J.,McDonough, M.A.,Schofield, C.J. (登録日: 2015-12-08, 公開日: 2016-08-10, 最終更新日: 2024-11-06)

主引用文献

Cahill, S.T.,Tarhonskaya, H.,Rydzik, A.M.,Flashman, E.,McDonough, M.A.,Schofield, C.J.,Brem, J.
Use of ferrous iron by metallo-beta-lactamases.
J. Inorg. Biochem., 163:185-193, 2016

PubMed Abstract: Metallo-β-lactamases (MBLs) catalyse the hydrolysis of almost all β-lactam antibacterials including the latest generation carbapenems and are a growing worldwide clinical problem. It is proposed that MBLs employ one or two zinc ion cofactors in vivo. Isolated MBLs are reported to use transition metal ions other than zinc, including copper, cadmium and manganese, with iron ions being a notable exception. We report kinetic and biophysical studies with the di-iron(II)-substituted metallo-β-lactamase II from Bacillus cereus (di-Fe(II) BcII) and the clinically relevant B1 subclass Verona integron-encoded metallo-β-lactamase 2 (di-Fe(II) VIM-2). The results reveal that MBLs can employ ferrous iron in catalysis, but with altered kinetic and inhibition profiles compared to the zinc enzymes. A crystal structure of di-Fe(II) BcII reveals only small overall changes in the active site compared to the di-Zn(II) enzyme including retention of the di-metal bridging water; however, the positions of the metal ions are altered in the di-Fe(II) compared to the di-Zn(II) structure. Stopped-flow analyses reveal that the mechanism of nitrocefin hydrolysis by both di-Fe(II) BcII and di-Fe(II) VIM-2 is altered compared to the di-Zn(II) enzymes. Notably, given that the MBLs are the subject of current medicinal chemistry efforts, the results raise the possibility the Fe(II)-substituted MBLs may be of clinical relevance under conditions of low zinc availability, and reveal potential variation in inhibitor activity against the differently metallated MBLs.

PubMed: 27498591
DOI: 10.1016/j.jinorgbio.2016.07.013

実験手法

X-RAY DIFFRACTION (1.1 Å)