5OEQ
Mycobacterium tuberculosis DprE1 in complex with inhibitor TCA020
Summary for 5OEQ
Entry DOI | 10.2210/pdb5oeq/pdb |
Related | 4KW5 5OEL 5OEP |
Descriptor | Decaprenylphosphoryl-beta-D-ribose oxidase, FLAVIN-ADENINE DINUCLEOTIDE, ~{N}-[3-(pyrimidin-2-ylcarbamoyl)thiophen-2-yl]-[1,3]thiazolo[4,5-c]pyridine-2-carboxamide, ... (5 entities in total) |
Functional Keywords | fad-containing oxidoreductase decaprenylphosphoarabinose synthesis, oxidoreductase |
Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
Total number of polymer chains | 2 |
Total formula weight | 106102.29 |
Authors | Futterer, K.,Batt, S.M.,Besra, G.S. (deposition date: 2017-07-09, release date: 2018-05-16, Last modification date: 2024-01-17) |
Primary citation | Liu, R.,Lyu, X.,Batt, S.M.,Hsu, M.H.,Harbut, M.B.,Vilcheze, C.,Cheng, B.,Ajayi, K.,Yang, B.,Yang, Y.,Guo, H.,Lin, C.,Gan, F.,Wang, C.,Franzblau, S.G.,Jacobs, W.R.,Besra, G.S.,Johnson, E.F.,Petrassi, M.,Chatterjee, A.K.,Futterer, K.,Wang, F. Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. Angew. Chem. Int. Ed. Engl., 56:13011-13015, 2017 Cited by PubMed Abstract: Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB. PubMed: 28815830DOI: 10.1002/anie.201707324 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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