Loading
PDBj
MenuPDBj@FacebookPDBj@TwitterPDBj@YouTubewwPDB FoundationwwPDB
RCSB PDBPDBeBMRBAdv. SearchSearch help

6HRW

EthR2 in complex with compound 1 (BDM14272)

Summary for 6HRW
Entry DOI10.2210/pdb6hrw/pdb
DescriptorProbable transcriptional regulatory protein, (1~{S},5~{R})-8-[2-(4-chlorophenyl)ethyl]-8-azabicyclo[3.2.1]octan-3-one (3 entities in total)
Functional Keywordshelix-turn-helix, tetr-family, complex, inhibitor, drug design, tuberculosis, ethionamide, dna binding protein
Biological sourceMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Total number of polymer chains2
Total formula weight48508.90
Authors
Wintjens, R.,Wohlkonig, A.,Tanina, A. (deposition date: 2018-09-28, release date: 2019-02-27, Last modification date: 2024-01-24)
Primary citationPrevet, H.,Moune, M.,Tanina, A.,Kemmer, C.,Herledan, A.,Frita, R.,Wohlkonig, A.,Bourotte, M.,Villemagne, B.,Leroux, F.,Gitzinger, M.,Baulard, A.R.,Deprez, B.,Wintjens, R.,Willand, N.,Flipo, M.
A fragment-based approach towards the discovery of N-substituted tropinones as inhibitors of Mycobacterium tuberculosis transcriptional regulator EthR2.
Eur J Med Chem, 167:426-438, 2019
Cited by
PubMed Abstract: Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis, represents one of the most challenging threat to public health worldwide, and with the increasing resistance to approved TB drugs, it is needed to develop new strategies to address this issue. Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant TB. It is a prodrug that requires activation by mycobacterial monooxygenases to inhibit the enoyl-ACP reductase InhA, which is involved in mycolic acid biosynthesis. Very recently, we identified that inhibition of a transcriptional repressor, termed EthR2, derepresses a new bioactivation pathway that results in the boosting of ethionamide activation. Herein, we describe the identification of potent EthR2 inhibitors using fragment-based screening and structure-based optimization. A target-based screening of a fragment library using thermal shift assay followed by X-ray crystallography identified 5 hits. Rapid optimization of the tropinone chemical series led to compounds with improved in vitro potency.
PubMed: 30784877
DOI: 10.1016/j.ejmech.2019.02.023
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.45 Å)
Structure validation

227111

PDB entries from 2024-11-06

PDB statisticsPDBj update infoContact PDBjnumon