6d51 | pdb_00006d51

Crystal structure of L,D-transpeptidase 3 from Mycobacterium tuberculosis in complex with a faropenem-derived adduct

spinqualitylabelsall models 6d51, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6d51 is a 1 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACE, CA Gene: Rv1433, RVBD_1433, P425_01489 (MYCTU) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [LDT3_MYCTU] Probable L,D-transpeptidase that may perform as-yet-unknown cross-linking reactions in M.tuberculosis. Is not able to generate 3->3 cross-links in peptidoglycan, using tetrapeptide stems as acyl donor substrates. May function in the anchoring of proteins to peptidoglycan. Publication Abstract from PubMed Targeting Mycobacterium tuberculosis peptidoglycans with beta-lactam antibiotics represents a strategy to address increasing resistance to antitubercular drugs. beta-Lactams inhibit peptidoglycan synthases such as l,d-transpeptidases, a group of carbapenem-sensitive enzymes that stabilize peptidoglycans through 3 --> 3 cross-links. M. tuberculosis encodes five l,d-transpeptidases (LdtMt1-5), of which LdtMt3 is one of the less understood. Herein, we structurally characterized the apo and faropenem-acylated forms of LdtMt3 at 1.3 and 1.8 A resolution, respectively. These structures revealed a fold and catalytic diad similar to those of other LdtsMt enzymes, supporting its involvement in transpeptidation reactions despite divergences in active site size and charges. The LdtMt3-faropenem structure indicated that faropenem is degraded after Cys-246 acylation, and possibly only a beta-OH-butyrate or an acetyl group (C2H3O) covalently attached to the enzyme remains, an observation that strongly supports the notion that LdtMt3 is inactivated by beta-lactams. Docking simulations with intact beta-lactams predicted key LdtMt3 residues that interact with these antibiotics. We also characterized the heat of acylation involved in the binding and reaction of LdtMt3 for ten beta-lactams belonging to four different classes, and imipenem had the highest inactivation constant. This work provides key insights into the structure, binding mechanisms, and degradation of beta-lactams by LdtMt3, which may be useful for the development of additional beta-lactams with potential antitubercular activity. Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by l,d-Transpeptidase 3 (LdtMt3) from Mycobacterium tuberculosis.,Libreros-Zuniga GA, Dos Santos Silva C, Salgado Ferreira R, Dias MVB ACS Infect Dis. 2019 Feb 8;5(2):260-271. doi: 10.1021/acsinfecdis.8b00244. Epub, 2018 Dec 28. PMID:30556998 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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