5LBG
Crystal structure of the Mycobacterium tuberculosis L,D-transpeptidase-2 (LdtMt2) BC-module with faropenem-derived adduct at the active site cysteine-354
Summary for 5LBG
| Entry DOI | 10.2210/pdb5lbg/pdb |
| Related | 4HUC |
| Descriptor | L,D-transpeptidase 2, (3S)-3-HYDROXYBUTANOIC ACID (3 entities in total) |
| Functional Keywords | cell wall, peptidoglycan, transpeptidase, mycobacterium tuberculosis, transferase |
| Biological source | Mycobacterium tuberculosis |
| Cellular location | Cell membrane ; Lipid-anchor : O53223 |
| Total number of polymer chains | 2 |
| Total formula weight | 57121.40 |
| Authors | Steiner, E.M.,Schnell, R.,Schneider, G. (deposition date: 2016-06-16, release date: 2017-01-18, Last modification date: 2024-11-06) |
| Primary citation | Steiner, E.M.,Schneider, G.,Schnell, R. Binding and processing of beta-lactam antibiotics by the transpeptidase LdtMt2 from Mycobacterium tuberculosis. FEBS J., 284:725-741, 2017 Cited by PubMed Abstract: β-lactam antibiotics represent a novel direction in the chemotherapy of tuberculosis that brings the peptidoglycan layer of the complex mycobacterial cell wall in focus as a therapeutic target. Peptidoglycan stability in Mycobacterium tuberculosis, especially during infection, relies on the nonconventional peptide cross-links formed by l,d-transpeptidases. These enzymes are known to be inhibited by β-lactams, primarily carbapenems, leading to a stable covalent modification at the enzyme active site. A panel of 16 β-lactam antibiotics was characterized by inhibition kinetics, mass spectrometry, and x-ray crystallography to identify efficient compounds and study their action on the essential transpeptidase, Ldt . Members of the carbapenem class displayed fast binding kinetics, but faropenem, a penem type compound showed a three to four time higher rate in the adduct formation. In three cases, mass spectrometry indicated that carbapenems may undergo decarboxylation, while faropenem decomposition following the acylation step results in a small 87 Da β-OH-butyryl adduct bound at the catalytic cysteine residue. The crystal structure of Ldt at 1.54 Å resolution with this fragment bound revealed that the protein adopts a closed conformation that shields the thioester bond from the solvent, which is in line with the high stability of this dead-end complex observed also in biochemical assays. PubMed: 28075068DOI: 10.1111/febs.14010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.54 Å) |
Structure validation
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