Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα).
RXRα
biochemical analysis
crystal structure
fragment molecular orbital theory
molecular dynamics simulations
partial agonist
Journal
FEBS letters
ISSN: 1873-3468
Titre abrégé: FEBS Lett
Pays: England
ID NLM: 0155157
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
18
09
2018
revised:
01
11
2018
accepted:
14
11
2018
pubmed:
20
12
2018
medline:
23
7
2019
entrez:
20
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30565665
doi: 10.1002/1873-3468.13301
doi:
Substances chimiques
1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid
0
Ligands
0
Retinoid X Receptor alpha
0
Tetrahydronaphthalenes
0
Triazoles
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
242-250Informations de copyright
© 2018 Federation of European Biochemical Societies.