5EZH

Structure of Transcriptional Regulatory Repressor Protein - EthR from Mycobacterium Tuberculosis in complex with compound 21 at 1.7A resolution

5EZH の概要

• エントリーDOI: 10.2210/pdb5ezh/pdb
• 分子名称: HTH-type transcriptional regulator EthR, ~{N}-[(1-pyridin-2-ylpiperidin-4-yl)methyl]pyrrolidine-1-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: ethr, transcription, repressor, mycobacterium tuberculosis
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25932.09

構造登録者

Surade, S.,Blaszczyk, M.,Nikiforov, P.O.,Abell, C.,Blundell, T.L. (登録日: 2015-11-26, 公開日: 2016-02-03, 最終更新日: 2024-01-10)

主引用文献

Nikiforov, P.O.,Surade, S.,Blaszczyk, M.,Delorme, V.,Brodin, P.,Baulard, A.R.,Blundell, T.L.,Abell, C.
A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.
Org.Biomol.Chem., 14:2318-2326, 2016

PubMed Abstract: With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.

PubMed: 26806381
DOI: 10.1039/c5ob02630j

実験手法

X-RAY DIFFRACTION (1.7 Å)