5MXK

Structure of Mycobacterium Tuberculosis Transcriptional Regulatory Repressor Protein (EthR) in complex with fragment 7G9.

Summary for 5MXK

• Entry DOI: 10.2210/pdb5mxk/pdb
• Descriptor: HTH-type transcriptional regulator EthR, ~{N}-(5-oxidanylidene-7,8-dihydro-6~{H}-naphthalen-2-yl)ethanamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: ethr, repressor, tetr, mycobacterium tuberculosis, transcription
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 24109.08

Authors

Mendes, V.,Chan, D.S.-H.,Thomas, S.E.,McConnell, B.,Matak-Vinkovic, D.,Coyne, A.G.,Abell, C.,Blundell, T.L. (deposition date: 2017-01-23, release date: 2017-05-31, Last modification date: 2024-01-17)

Primary citation

Chan, D.S.,Mendes, V.,Thomas, S.E.,McConnell, B.N.,Matak-Vinkovic, D.,Coyne, A.G.,Blundell, T.L.,Abell, C.
Fragment Screening against the EthR-DNA Interaction by Native Mass Spectrometry.
Angew. Chem. Int. Ed. Engl., 56:7488-7491, 2017

PubMed Abstract: Native nanoelectrospray ionization mass spectrometry is an underutilized technique for fragment screening. In this study, the first demonstration is provided of the use of native mass spectrometry for screening fragments against a protein-DNA interaction. EthR is a transcriptional repressor of EthA expression in Mycobacterium tuberculosis (Mtb) that reduces the efficacy of ethionamide, a second-line antitubercular drug used to combat multidrug-resistant Mtb strains. A small-scale fragment screening campaign was conducted against the EthR-DNA interaction using native mass spectrometry, and the results were compared with those from differential scanning fluorimetry, a commonly used primary screening technique. Hits were validated by surface plasmon resonance and X-ray crystallography. The screening campaign identified two new fragments that disrupt the EthR-DNA interaction in vitro (IC =460-610 μm) and bind to the hydrophobic channel of the EthR dimer.

PubMed: 28513917
DOI: 10.1002/anie.201702888

Experimental method

X-RAY DIFFRACTION (1.932 Å)