3O8G

EthR from Mycobacterium tuberculosis in complex with compound BDM14801

Summary for 3O8G

• Entry DOI: 10.2210/pdb3o8g/pdb
• Related: 1U9N 3O8H
• Descriptor: TRANSCRIPTIONAL REGULATORY REPRESSOR PROTEIN (TETR-FAMILY) ETHR, 1-(azidoacetyl)-4-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)piperidine (3 entities in total)
• Functional Keywords: tetr-family, transcritptional regulatory repressor, inhibitor, dna, dna binding protein, transcription repressor-inhibitor complex, transcription repressor/inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 26271.43

Authors

Willand, N.,Desroses, M.,Toto, P.,Diri, B.,Lens, Z.,Villeret, V.,Rucktooa, P.,Locht, C.,Baulard, A.,Deprez, B. (deposition date: 2010-08-03, release date: 2010-09-01, Last modification date: 2024-02-21)

Primary citation

Willand, N.,Desroses, M.,Toto, P.,Dirie, B.,Lens, Z.,Villeret, V.,Rucktooa, P.,Locht, C.,Baulard, A.,Deprez, B.
Exploring drug target flexibility using in situ click chemistry: application to a mycobacterial transcriptional regulator.
Acs Chem.Biol., 5:1007-1013, 2010

PubMed Abstract: In situ click chemistry has been successfully applied to probe the ligand binding domain of EthR, a mycobacterial transcriptional regulator known to control the sensitivity of Mycobacterium tuberculosis to several antibiotics. Specific protein-templated ligands were generated in situ from one azide and six clusters of 10 acetylenic fragments. Comparative X-ray structures of EthR complexed with either clicked ligand BDM14950 or its azide precursor showed ligand-dependent conformational impacts on the protein architecture. This approach revealed two mobile phenylalanine residues that control the access to a previously hidden hydrophobic pocket that can be further exploited for the development of structurally diverse EthR inhibitors. This report shows that protein-directed in situ chemistry allows medicinal chemists to explore the conformational space of a ligand-binding pocket and is thus a valuable tool to guide drug design in the complex path of hit-to-lead processes.

PubMed: 20704273
DOI: 10.1021/cb100177g

Experimental method

X-RAY DIFFRACTION (1.9 Å)