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Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α ( RXR α)
Author(s) -
Miyashita Yurina,
Numoto Nobutaka,
Arulmozhiraja Sundaram,
Nakano Shogo,
Matsuo Naoya,
Shimizu Kanade,
Shibahara Osamu,
Fujihara Michiko,
Kakuta Hiroki,
Ito Sohei,
Ikura Teikichi,
Ito Nobutoshi,
Tokiwa Hiroaki
Publication year - 2019
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13301
Subject(s) - partial agonist , retinoid x receptor , tetramer , ligand (biochemistry) , chemistry , agonistic behaviour , inverse agonist , agonist , stereochemistry , receptor , biophysics , nuclear receptor , biochemistry , biology , medicine , psychiatry , transcription factor , gene , enzyme , aggression
1‐[(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydronaphthalen‐2‐yl)amino]benzotriazole‐5‐carboxylic acid (CBt‐PMN), a partial agonist of retinoid X receptor ( RXR ), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CB t‐ PMN ‐bound ligand‐binding domain of human RXR α ( hRXR α) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CB t‐ PMN s are clearly found binding in two different conformations. The dynamics of the hRXR α/ CB t‐ PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF ‐2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CB t‐ PMN in the complex is probably the reason behind its partial agonistic activity.