5XDS
Crystal structure of Mycobacterium tuberculosis HisB bound with an inhibitor
Summary for 5XDS
| Entry DOI | 10.2210/pdb5xds/pdb |
| Descriptor | Imidazoleglycerol-phosphate dehydratase, MANGANESE (II) ION, CHLORIDE ION, ... (5 entities in total) |
| Functional Keywords | mycobacterium tuberculosis, tuberculosis, imidazoleglycerol phosphate dehydratase, drug target, lyase-lyase inhibitor complex, lyase/lyase inhibitor |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Cellular location | Cytoplasm : P9WML9 |
| Total number of polymer chains | 1 |
| Total formula weight | 23934.99 |
| Authors | Kumar, D.,Jha, B.,Ahangar, M.S.,Kumar, B.B. (deposition date: 2017-03-29, release date: 2018-04-04, Last modification date: 2023-11-22) |
| Primary citation | Kumar, D.,Jha, B.,Bhatia, I.,Ashraf, A.,Dwivedy, A.,Biswal, B.K. Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol-phosphate dehydratase. Proteins, 2021 Cited by PubMed Abstract: Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), employs ten enzymes including imidazoleglycerol-phosphate dehydratase (IGPD) for de novo biosynthesis of histidine. The absence of histidine-biosynthesis in humans combined with its essentiality for Mtb makes the enzymes of this pathway major anti-TB drug targets. We explored the inhibitory potential of a small molecule β-(1,2,4-Triazole-3-yl)-DL-alanine (DLA) against Mtb IGPD. DLA exhibits an in vitro inhibitory efficacy in the lower micromolar range. Higher-resolution crystal structures of native and substrate-bound Mtb IGPD provided additional structural features of this important drug target. Crystal structure of IGPD-DLA complex at a resolution of 1.75 Å, confirmed that DLA locks down the function of the enzyme by binding in the active site pocket of the IGPD mimicking the substrate-binding mode to a high degree. In our biochemical study, DLA showed an efficient inhibition of Mtb IGPD. Furthermore, DLA also showed bactericidal activity against Mtb and Mycobacterium smegmatis and inhibited their growth in respective culture medium. Importantly, owing to the favorable ADME and physicochemical properties, it serves as an important lead molecule for further derivatizations. PubMed: 34288118DOI: 10.1002/prot.26181 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.75 Å) |
Structure validation
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