8A1O

Crystal structure of the transpeptidase LdtMt2 from Mycobacterium tuberculosis in complex with acrylamide analogue 8

8A1O の概要

• エントリーDOI: 10.2210/pdb8a1o/pdb
• 分子名称: L,D-transpeptidase 2, DIMETHYL SULFOXIDE, GLYCEROL, ... (8 entities in total)
• 機能のキーワード: l, d-transpeptidase, ldtmt2, inhibitor, covalent, antimicrobial protein
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38736.60

構造登録者

de Munnik, M.,Lang, P.A.,Brem, J.,Schofield, C.J. (登録日: 2022-06-01, 公開日: 2023-06-14, 最終更新日: 2024-11-13)

主引用文献

de Munnik, M.,Lang, P.A.,De Dios Anton, F.,Cacho, M.,Bates, R.H.,Brem, J.,Rodriguez Miquel, B.,Schofield, C.J.
High-throughput screen with the l,d-transpeptidase Ldt Mt2 of Mycobacterium tuberculosis reveals novel classes of covalently reacting inhibitors.
Chem Sci, 14:7262-7278, 2023

PubMed Abstract: Disruption of bacterial cell wall biosynthesis in is a promising target for treating tuberculosis. The l,d-transpeptidase Ldt, which is responsible for the formation of 3 → 3 cross-links in the cell wall peptidoglycan, has been identified as essential for virulence. We optimised a high-throughput assay for Ldt, and screened a targeted library of ∼10 000 electrophilic compounds. Potent inhibitor classes were identified, including established (, β-lactams) and unexplored covalently reacting electrophilic groups (, cyanamides). Protein-observed mass spectrometric studies reveal most classes to react covalently and irreversibly with the Ldt catalytic cysteine (Cys354). Crystallographic analyses of seven representative inhibitors reveal induced fit involving a loop enclosing the Ldt active site. Several of the identified compounds have a bactericidal effect on within macrophages, one with an MIC value of ∼1 μM. The results provide leads for the development of new covalently reaction inhibitors of Ldt and other nucleophilic cysteine enzymes.

PubMed: 37416715
DOI: 10.1039/d2sc06858c

実験手法

X-RAY DIFFRACTION (1.95 Å)