5OEP

Mycobacterium tuberculosis DprE1 in complex with inhibitor TCA481

5OEP の概要

• エントリーDOI: 10.2210/pdb5oep/pdb
• 関連するPDBエントリー: 4KW5 5OEL
• 分子名称: Decaprenylphosphoryl-beta-D-ribose oxidase, FLAVIN-ADENINE DINUCLEOTIDE, ethyl ~{N}-[2-(1,3-benzothiazol-2-ylcarbonylamino)-5-fluoranyl-thiophen-3-yl]carbonylcarbamate, ... (5 entities in total)
• 機能のキーワード: fad-containing oxidoreductase decaprenylphosphoarabinose synthesis, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• 細胞内の位置: Periplasm : P9WJF1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106506.70

構造登録者

Futterer, K.,Batt, S.M.,Besra, G.S. (登録日: 2017-07-09, 公開日: 2018-05-16, 最終更新日: 2024-01-17)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (2.35 Å)