5NQ5
Mtb TMK crystal structure in complex with compound 1
Summary for 5NQ5
| Entry DOI | 10.2210/pdb5nq5/pdb |
| Descriptor | Thymidylate kinase, 5-methyl-1-[(3~{S})-1-[(3-phenoxyphenyl)methyl]piperidin-3-yl]pyrimidine-2,4-dione (2 entities in total) |
| Functional Keywords | thymidylate kinase, nucleotide binding, inhibitor, transferase |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 23053.99 |
| Authors | Merceron, R.,Song, L.,Munier-Lehmann, H.,Van Calenbergh, S.,Savvides, S. (deposition date: 2017-04-19, release date: 2018-03-21, Last modification date: 2024-01-17) |
| Primary citation | Song, L.,Merceron, R.,Gracia, B.,Quintana, A.L.,Risseeuw, M.D.P.,Hulpia, F.,Cos, P.,Ainsa, J.A.,Munier-Lehmann, H.,Savvides, S.N.,Van Calenbergh, S. Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors. J. Med. Chem., 61:2753-2775, 2018 Cited by PubMed Abstract: In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance. PubMed: 29510037DOI: 10.1021/acs.jmedchem.7b01570 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.85 Å) |
Structure validation
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