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5OEQ

Mycobacterium tuberculosis DprE1 in complex with inhibitor TCA020

Summary for 5OEQ
Entry DOI10.2210/pdb5oeq/pdb
Related4KW5 5OEL 5OEP
DescriptorDecaprenylphosphoryl-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 Keywordsfad-containing oxidoreductase decaprenylphosphoarabinose synthesis, oxidoreductase
Biological sourceMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Total number of polymer chains2
Total formula weight106102.29
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 citationLiu, 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: 28815830
DOI: 10.1002/anie.201707324
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.25 Å)
Structure validation

226707

數據於2024-10-30公開中

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