4KW5

M. tuberculosis DprE1 in complex with inhibitor TCA1

4KW5 の概要

• エントリーDOI: 10.2210/pdb4kw5/pdb
• 関連するPDBエントリー: 4FDN 4FDO 4FDP 4FEH 4FF6
• 分子名称: Oxidoreductase, FLAVIN-ADENINE DINUCLEOTIDE, ethyl ({2-[(1,3-benzothiazol-2-ylcarbonyl)amino]thiophen-3-yl}carbonyl)carbamate, ... (6 entities in total)
• 機能のキーワード: alpha/beta fold, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 103107.27

構造登録者

Batt, S.M.,Besra, G.S.,Futterer, K. (登録日: 2013-05-23, 公開日: 2013-07-10, 最終更新日: 2023-09-20)

主引用文献

Wang, F.,Sambandan, D.,Halder, R.,Wang, J.,Batt, S.M.,Weinrick, B.,Ahmad, I.,Yang, P.,Zhang, Y.,Kim, J.,Hassani, M.,Huszar, S.,Trefzer, C.,Ma, Z.,Kaneko, T.,Mdluli, K.E.,Franzblau, S.,Chatterjee, A.K.,Johnson, K.,Mikusova, K.,Besra, G.S.,Futterer, K.,Jacobs, W.R.,Schultz, P.G.
Identification of a small molecule with activity against drug-resistant and persistent tuberculosis.
Proc.Natl.Acad.Sci.USA, 110:E2510-E2517, 2013

PubMed Abstract: A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.

PubMed: 23776209
DOI: 10.1073/pnas.1309171110

実験手法

X-RAY DIFFRACTION (2.612 Å)