5MYS

Structure of Transcriptional Regulatory Repressor Protein - EthR from Mycobacterium Tuberculosis in complex with compound GSK920684A at 1.59A resolution

Summary for 5MYS

• Entry DOI: 10.2210/pdb5mys/pdb
• Descriptor: HTH-type transcriptional regulator EthR, 2-(3-fluoranylphenoxy)-~{N}-(4-pyridin-2-yl-1,3-thiazol-2-yl)ethanamide (3 entities in total)
• Functional Keywords: ethr, mycobacterium tuberculosis, transcription, represor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 25588.60

Authors

Blaszczyk, M.,Mendes, V.,Mugumbate, G.,Blundell, T.L. (deposition date: 2017-01-27, release date: 2017-10-25, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.587 Å)