par Willand, Nicolas;Desroses, Matthieu;Toto, Patrick;Dirié, Bertrand;Lens, Zoé ;Villeret, Vincent ;Rucktooa, Prakash;Locht, Camille ;Baulard, Alain;Déprez, Benoit
Référence A C S Chemical Biology, 5, 11, page (1007-1013)
Publication Publié, 2010-11
Référence A C S Chemical Biology, 5, 11, page (1007-1013)
Publication Publié, 2010-11
Article révisé par les pairs
Résumé : | 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. © 2010 American Chemical Society. |