5MYM

Structure of Transcriptional Regulatory Repressor Protein - EthR from Mycobacterium Tuberculosis in complex with compound GSK2032710A at 2.28A resolution

5MYM の概要

• エントリーDOI: 10.2210/pdb5mym/pdb
• 分子名称: HTH-type transcriptional regulator EthR, [4-(phenylmethyl)piperidin-1-yl]-[1-(5-pyrrol-1-yl-1,3,4-thiadiazol-2-yl)piperidin-4-yl]methanone, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: ethr, mycobacterium tuberculosis, transcription, represor
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 102156.46

構造登録者

Mendes, V.,Blaszczyk, M.,Mugumbate, G.,Blundell, T.L. (登録日: 2017-01-27, 公開日: 2017-10-25, 最終更新日: 2024-01-17)

主引用文献

Mugumbate, G.,Mendes, V.,Blaszczyk, M.,Sabbah, M.,Papadatos, G.,Lelievre, J.,Ballell, L.,Barros, D.,Abell, C.,Blundell, T.L.,Overington, J.P.
Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach.
Front Pharmacol, 8:681-681, 2017

PubMed Abstract: Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC below 50 μM against EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.

PubMed: 29018348
DOI: 10.3389/fphar.2017.00681

実験手法

X-RAY DIFFRACTION (2.28 Å)