8A1J

Crystal structure of the transpeptidase LdtMt2 from Mycobacterium tuberculosis in complex with maleimide analogue 3

Summary for 8A1J

• Entry DOI: 10.2210/pdb8a1j/pdb
• Descriptor: L,D-transpeptidase 2, DIMETHYL SULFOXIDE, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: l, d-transpeptidase, ldtmt2, inhibitor, covalent, antimicrobial protein
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 76695.06

Authors

de Munnik, M.,Lang, P.A.,Brem, J.,Schofield, C.J. (deposition date: 2022-06-01, release date: 2023-06-14, Last modification date: 2024-02-07)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.55 Å)