5ZQU

Crystal structure of tetrameric RXRalpha-LBD complexed with partial agonist CBt-PMN

Summary for 5ZQU

• Entry DOI: 10.2210/pdb5zqu/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, 1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)benzotriazole-5-carboxylic acid, BROMIDE ION, ... (4 entities in total)
• Functional Keywords: extended form, multiple conformation, nuclear receptor, retinoid x receptor, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 111556.83

Authors

Miyashita, Y.,Numoto, N.,Arulmozhiraja, S.,Nakano, S.,Matsuo, N.,Shimizu, K.,Kakuta, H.,Ito, S.,Ikura, T.,Ito, N.,Tokiwa, H. (deposition date: 2018-04-20, release date: 2019-02-27, Last modification date: 2024-10-16)

Primary citation

Miyashita, Y.,Numoto, N.,Arulmozhiraja, S.,Nakano, S.,Matsuo, N.,Shimizu, K.,Shibahara, O.,Fujihara, M.,Kakuta, H.,Ito, S.,Ikura, T.,Ito, N.,Tokiwa, H.
Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor alpha (RXR alpha ).
FEBS Lett., 593:242-250, 2019

PubMed Abstract: 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.

PubMed: 30565665
DOI: 10.1002/1873-3468.13301

Experimental method

X-RAY DIFFRACTION (2.60038789589 Å)