5LBG

Crystal structure of the Mycobacterium tuberculosis L,D-transpeptidase-2 (LdtMt2) BC-module with faropenem-derived adduct at the active site cysteine-354

5LBG の概要

• エントリーDOI: 10.2210/pdb5lbg/pdb
• 関連するPDBエントリー: 4HUC
• 分子名称: L,D-transpeptidase 2, (3S)-3-HYDROXYBUTANOIC ACID (3 entities in total)
• 機能のキーワード: cell wall, peptidoglycan, transpeptidase, mycobacterium tuberculosis, transferase
• 由来する生物種: Mycobacterium tuberculosis
• 細胞内の位置: Cell membrane ; Lipid-anchor : O53223
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57121.40

構造登録者

Steiner, E.M.,Schnell, R.,Schneider, G. (登録日: 2016-06-16, 公開日: 2017-01-18, 最終更新日: 2024-11-06)

主引用文献

Steiner, E.M.,Schneider, G.,Schnell, R.
Binding and processing of beta-lactam antibiotics by the transpeptidase LdtMt2 from Mycobacterium tuberculosis.
FEBS J., 284:725-741, 2017

PubMed Abstract: β-lactam antibiotics represent a novel direction in the chemotherapy of tuberculosis that brings the peptidoglycan layer of the complex mycobacterial cell wall in focus as a therapeutic target. Peptidoglycan stability in Mycobacterium tuberculosis, especially during infection, relies on the nonconventional peptide cross-links formed by l,d-transpeptidases. These enzymes are known to be inhibited by β-lactams, primarily carbapenems, leading to a stable covalent modification at the enzyme active site. A panel of 16 β-lactam antibiotics was characterized by inhibition kinetics, mass spectrometry, and x-ray crystallography to identify efficient compounds and study their action on the essential transpeptidase, Ldt . Members of the carbapenem class displayed fast binding kinetics, but faropenem, a penem type compound showed a three to four time higher rate in the adduct formation. In three cases, mass spectrometry indicated that carbapenems may undergo decarboxylation, while faropenem decomposition following the acylation step results in a small 87 Da β-OH-butyryl adduct bound at the catalytic cysteine residue. The crystal structure of Ldt at 1.54 Å resolution with this fragment bound revealed that the protein adopts a closed conformation that shields the thioester bond from the solvent, which is in line with the high stability of this dead-end complex observed also in biochemical assays.

PubMed: 28075068
DOI: 10.1111/febs.14010

実験手法

X-RAY DIFFRACTION (1.54 Å)