TY - JOUR
T1 - Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα)
AU - Miyashita, Yurina
AU - Numoto, Nobutaka
AU - Arulmozhiraja, Sundaram
AU - Nakano, Shogo
AU - Matsuo, Naoya
AU - Shimizu, Kanade
AU - Shibahara, Osamu
AU - Fujihara, Michiko
AU - Kakuta, Hiroki
AU - Ito, Sohei
AU - Ikura, Teikichi
AU - Ito, Nobutoshi
AU - Tokiwa, Hiroaki
N1 - Funding Information:
We thank Prof. Dr. Hiroyuki Kagechika of Tokyo Medical and Dental University for providing PA452. The synchrotron radiation experiments were performed under the approval of the Photon Factory Program Advisory Committee (proposal no. 2016G638 and 2017G514) and the Japan Synchrotron Radiation Research Institute (proposal no. 2017A2584). Computations were performed using the Research Center for Computational Science, Okazaki, and the facilities of the Supercomputer Center, the Institute for Solid State Physics, at the University of Tokyo. This work was supported by AMED-CREST #JP18gm0910003, and Nanken-Kyoten, TMDU.
Funding Information:
This work was supported by AMED-CREST #JP18gm0910003, and Nanken-Kyoten, TMDU.
PY - 2019/1
Y1 - 2019/1
N2 - 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 CBt-PMN-bound ligand-binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt-PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt-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 CBt-PMN in the complex is probably the reason behind its partial agonistic activity.
AB - 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 CBt-PMN-bound ligand-binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt-PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt-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 CBt-PMN in the complex is probably the reason behind its partial agonistic activity.
KW - RXRα
KW - biochemical analysis
KW - crystal structure
KW - fragment molecular orbital theory
KW - molecular dynamics simulations
KW - partial agonist
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U2 - 10.1002/1873-3468.13301
DO - 10.1002/1873-3468.13301
M3 - Article
C2 - 30565665
AN - SCOPUS:85058935730
VL - 593
SP - 242
EP - 250
JO - FEBS Letters
JF - FEBS Letters
SN - 0014-5793
IS - 2
ER -
