3O8H

EthR from Mycobacterium tuberculosis in complex with compound BDM14950

Summary for 3O8H

• Entry DOI: 10.2210/pdb3o8h/pdb
• Related: 1U9N 3O8G
• Descriptor: Transcriptional Regulatory Repressor protein (TETR-Family) EthR, 4-iodo-N-[(1-{2-oxo-2-[4-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]ethyl}-1H-1,2,3-triazol-4-yl)methyl]benzenesulfonamide (3 entities in total)
• Functional Keywords: tetr-family, transcriptional regulatory repressor, dna, transcription
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 26592.57

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)