6D51
Crystal structure of L,D-transpeptidase 3 from Mycobacterium tuberculosis in complex with a faropenem-derived adduct
Summary for 6D51
| Entry DOI | 10.2210/pdb6d51/pdb |
| Descriptor | Probable L,D-transpeptidase 3, ACETYL GROUP, CALCIUM ION, ... (4 entities in total) |
| Functional Keywords | adduct, transferase |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 1 |
| Total formula weight | 28037.38 |
| Authors | Libreros, G.A.,Dias, M.V.B. (deposition date: 2018-04-19, release date: 2019-02-27, Last modification date: 2023-10-04) |
| Primary citation | Libreros-Zuniga, G.A.,Dos Santos Silva, C.,Salgado Ferreira, R.,Dias, M.V.B. Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by l,d-Transpeptidase 3 (LdtMt3) from Mycobacterium tuberculosis. ACS Infect Dis, 5:260-271, 2019 Cited by PubMed Abstract: Targeting Mycobacterium tuberculosis peptidoglycans with β-lactam antibiotics represents a strategy to address increasing resistance to antitubercular drugs. β-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 (Ldt), of which Ldt is one of the less understood. Herein, we structurally characterized the apo and faropenem-acylated forms of Ldt at 1.3 and 1.8 Å resolution, respectively. These structures revealed a fold and catalytic diad similar to those of other Ldts enzymes, supporting its involvement in transpeptidation reactions despite divergences in active site size and charges. The Ldt-faropenem structure indicated that faropenem is degraded after Cys-246 acylation, and possibly only a β-OH-butyrate or an acetyl group (CHO) covalently attached to the enzyme remains, an observation that strongly supports the notion that Ldt is inactivated by β-lactams. Docking simulations with intact β-lactams predicted key Ldt residues that interact with these antibiotics. We also characterized the heat of acylation involved in the binding and reaction of Ldt for ten β-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 β-lactams by Ldt, which may be useful for the development of additional β-lactams with potential antitubercular activity. PubMed: 30556998DOI: 10.1021/acsinfecdis.8b00244 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.83 Å) |
Structure validation
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