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

doi:10.1002/1873-3468.13301

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 journal › Article › peer-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 language	English
Pages (from-to)	242-250
Number of pages	9
Journal	FEBS Letters
Volume	593
Issue number	2
DOIs	https://doi.org/10.1002/1873-3468.13301
Publication status	Published - Jan 2019
Externally published	Yes

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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Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα). / Miyashita, Yurina; Numoto, Nobutaka; Arulmozhiraja, Sundaram; Nakano, Shogo; Matsuo, Naoya; Shimizu, Kanade; Shibahara, Osamu; Fujihara, Michiko; Kakuta, Hiroki; Ito, Sohei; Ikura, Teikichi; Ito, Nobutoshi; Tokiwa, Hiroaki.

In: FEBS Letters, Vol. 593, No. 2, 01.2019, p. 242-250.

Research output: Contribution to journal › Article › peer-review

Miyashita, Yurina ; Numoto, Nobutaka ; Arulmozhiraja, Sundaram ; Nakano, Shogo ; Matsuo, Naoya ; Shimizu, Kanade ; Shibahara, Osamu ; Fujihara, Michiko ; Kakuta, Hiroki ; Ito, Sohei ; Ikura, Teikichi ; Ito, Nobutoshi ; Tokiwa, Hiroaki. / Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα). In: FEBS Letters. 2019 ; Vol. 593, No. 2. pp. 242-250.

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AU - Matsuo, Naoya

AU - Shimizu, Kanade

AU - Shibahara, Osamu

AU - Fujihara, Michiko

AU - Kakuta, Hiroki

AU - Ito, Sohei

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AU - Ito, Nobutoshi

AU - Tokiwa, Hiroaki

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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.

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