8a1m

Crystal structure of the transpeptidase LdtMt2 from Mycobacterium tuberculosis in complex with maleimide analogue 4

spinqualitylabelsall models 8a1m, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8a1m is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: CL, DMS, EDO, GOL, KUL, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Disruption of bacterial cell wall biosynthesis in Mycobacterium tuberculosis is a promising target for treating tuberculosis. The l,d-transpeptidase Ldt(Mt2), which is responsible for the formation of 3 --> 3 cross-links in the cell wall peptidoglycan, has been identified as essential for M. tuberculosis virulence. We optimised a high-throughput assay for Ldt(Mt2), and screened a targeted library of approximately 10 000 electrophilic compounds. Potent inhibitor classes were identified, including established (e.g., beta-lactams) and unexplored covalently reacting electrophilic groups (e.g., cyanamides). Protein-observed mass spectrometric studies reveal most classes to react covalently and irreversibly with the Ldt(Mt2) catalytic cysteine (Cys354). Crystallographic analyses of seven representative inhibitors reveal induced fit involving a loop enclosing the Ldt(Mt2) active site. Several of the identified compounds have a bactericidal effect on M. tuberculosis within macrophages, one with an MIC(50) value of approximately 1 muM. The results provide leads for the development of new covalently reaction inhibitors of Ldt(Mt2) and other nucleophilic cysteine enzymes. High-throughput screen with the l,d-transpeptidase Ldt(Mt2) of Mycobacterium tuberculosis reveals novel classes of covalently reacting inhibitors.,de Munnik M, Lang PA, De Dios Anton F, Cacho M, Bates RH, Brem J, Rodriguez Miquel B, Schofield CJ Chem Sci. 2023 May 30;14(26):7262-7278. doi: 10.1039/d2sc06858c. eCollection 2023 , Jul 5. PMID:37416715 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA