4QHC

Structure of M.Tuberculosis Betalactamase (Blac) with inhibitor having novel mechanism

4QHC の概要

• エントリーDOI: 10.2210/pdb4qhc/pdb
• 関連するPDBエントリー: 4DF6 4Q8I 4QB8
• 分子名称: Beta-lactamase, (3R,6R,7S)-7-[(2R,3aR)-hexahydropyrazolo[1,5-c][1,3]thiazin-2-yl]-6-(hydroxymethyl)-1,4-thiazepane-3-carboxylic acid, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: betalactam, betalactamase, penems, drug resistance, novel mechanism, qm/mm, 3-layer sandwich, dd-peptidase, beta-lactamase super family, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• 細胞内の位置: Cell inner membrane : P9WKD3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28867.21

構造登録者

Hazra, S.,Blanchard, J. (登録日: 2014-05-28, 公開日: 2015-07-22, 最終更新日: 2024-02-28)

主引用文献

Hazra, S.,Kurz, S.G.,Wolff, K.,Nguyen, L.,Bonomo, R.A.,Blanchard, J.S.
Kinetic and Structural Characterization of the Interaction of 6-Methylidene Penem 2 with the beta-Lactamase from Mycobacterium tuberculosis.
Biochemistry, 54:5657-5664, 2015

PubMed Abstract: Mycobacterium tuberculosis is intrinsically resistant to most β-lactam antibiotics because of the constitutive expression of the blaC-encoded β-lactamase. This enzyme has extremely high activity against penicillins and cephalosporins, but weaker activity against carbapenems. The enzyme can be inhibited by clavulanate, avibactam, and boronic acids. In this study, we investigated the ability of 6-methylidene β-lactams to inhibit BlaC. One such compound, penem 2, inhibited BlaC more than 70 times more efficiently than clavulanate. The compound forms a covalent complex with BlaC as shown by mass spectrometry. Crystallization of the complex revealed that the bound inhibitor was covalently attached via the Ser70 active site residue and that the covalently, acylated form of the inhibitor had undergone additional chemistry yielding a 4,7-thiazepine ring in place of the β-lactam and a thiazapyroline ring generated as a result of β-lactam ring opening. The stereochemistry of the product of the 7-endo-trig cyclization was the opposite of that observed previously for class A and D β-lactamases. Addition of penem 2 greatly synergized the antibacterial properties of both ampicillin and meropenem against a growing culture of M. tuberculosis. Strikingly, penem 2 alone showed significant growth inhibition, suggesting that in addition to its capability of efficiently inhibiting BlaC, it also inhibited the peptidoglycan cross-linking transpeptidases.

PubMed: 26237118
DOI: 10.1021/acs.biochem.5b00698

実験手法

X-RAY DIFFRACTION (1.899 Å)