5NIM

EthR complex

5NIM の概要

• エントリーDOI: 10.2210/pdb5nim/pdb
• 分子名称: HTH-type transcriptional regulator EthR, [1-(2-hydroxyethyl)pyrrolo[3,4-c]pyrazol-5-yl]-(5-propyl-1,2-oxazol-3-yl)methanone, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: tetr repressor, dna binding protein, protein ligand complex
• 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: 24166.07

構造登録者

Pohl, E.,Tatum, N.J.,Cole, J.C.,Baulard, A.R. (登録日: 2017-03-24, 公開日: 2017-11-15, 最終更新日: 2025-10-01)

主引用文献

Tatum, N.J.,Liebeschuetz, J.W.,Cole, J.C.,Frita, R.,Herledan, A.,Baulard, A.R.,Willand, N.,Pohl, E.
New active leads for tuberculosis booster drugs by structure-based drug discovery.
Org. Biomol. Chem., 15:10245-10255, 2017

PubMed Abstract: The transcriptional repressor EthR from Mycobacterium tuberculosis, a member of the TetR family of prokaryotic homo-dimeric transcription factors, controls the expression of the mycobacterial mono-oxygenase EthA. EthA is responsible for the bio-activation of the second-line tuberculosis pro-drug ethionamide, and consequently EthR inhibitors boost drug efficacy. Here, we present a comprehensive in silico structure-based screening protocol that led to the identification of a number of novel scaffolds of EthR inhibitors in subsequent biophysical screening by thermal shift assay. Growth inhibition assays demonstrated that five of the twenty biophysical hits were capable of boosting ethionamide activity in vitro, with the best novel scaffold displaying an EC of 34 μM. In addition, the co-crystal structures of EthR with four new ligands at resolution ranging from 2.1 to 1.4 Å confirm the binding and inactivation mode, and will enable future lead development.

PubMed: 29182187
DOI: 10.1039/c7ob00910k

実験手法

X-RAY DIFFRACTION (1.5 Å)