Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα)

Yurina Miyashita, Nobutaka Numoto, Sundaram Arulmozhiraja, Shogo Nakano, Naoya Matsuo, Kanade Shimizu, Osamu Shibahara, Michiko Fujihara, Hiroki Kakuta, Sohei Ito, Teikichi Ikura, Nobutoshi Ito, Hiroaki Tokiwa

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)242-250
Number of pages9
JournalFEBS Letters
Volume593
Issue number2
DOIs
Publication statusPublished - Jan 2019
Externally publishedYes

Keywords

  • RXRα
  • biochemical analysis
  • crystal structure
  • fragment molecular orbital theory
  • molecular dynamics simulations
  • partial agonist

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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