Journal
FEBS LETTERS
Volume 593, Issue 2, Pages 242-250Publisher
WILEY
DOI: 10.1002/1873-3468.13301
Keywords
biochemical analysis; crystal structure; fragment molecular orbital theory; molecular dynamics simulations; partial agonist; RXR alpha
Funding
- AMED-CREST [JP18gm0910003]
- Nanken-Kyoten, TMDU
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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 RXR alpha (hRXR alpha) 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 hRXR alpha/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.
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