Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function

doi:10.1073/pnas.0705356104

Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function

*Institut National de la Santé et de la Recherche Médicale, U554, 34090 Montpellier, France;
^†Université Montpellier 1 et 2, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5048, Centre de Biochimie Structurale, 34090 Montpellier, France;
^‡Departamento de Química Orgánica, Facultad de Química, Universidade de Vigo, 36310 Vigo, Spain;
^§Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, France; and
^¶Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Via L. De Crecchio 7, 80138 Napoli, Italy

Edited by Keith R. Yamamoto, University of California, San Francisco, CA, and approved September 10, 2007 (received for review June 7, 2007)

Abstract

Retinoid X receptors (RXRα, -β, and -γ) occupy a central position in the nuclear receptor superfamily, because they form heterodimers with many other family members and hence are involved in the control of a variety of (patho)physiologic processes. Selective RXR ligands, referred to as rexinoids, are already used or are being developed for cancer therapy and have promise for the treatment of metabolic diseases. However, important side effects remain associated with existing rexinoids. Here we describe the rational design and functional characterization of a spectrum of RXR modulators ranging from partial to pure antagonists and demonstrate their utility as tools to probe the implication of RXRs in cell biological phenomena. One of these ligands renders RXR activity particularly sensitive to coactivator levels and has the potential to act as a cell-specific RXR modulator. A combination of crystallographic and fluorescence anisotropy studies reveals the molecular details accounting for the agonist-to-antagonist transition and provides direct experimental evidence for a correlation between the pharmacological activity of a ligand and its impact on the structural dynamics of the activation helix H12. Using RXR and its cognate ligands as a model system, our correlative analysis of 3D structures and dynamic data provides an original view on ligand actions and enables the establishment of mechanistic concepts, which will aid in the development of selective nuclear receptor modulators.

Footnotes

**To whom correspondence may be addressed. E-mail: hg{at}igbmc.u-strasbg.fr, qolera{at}uvigo.es, or bourguet{at}cbs.cnrs.fr
Author contributions: V.N., E.P., and P.G. contributed equally to this work; P.G., H.G., A.R.d.L., and W.B. designed research; V.N., E.P., P.G., F.R.-B., F.M., S.K., G.L., O.H., C.A.R., and W.B. performed research; E.P. contributed new reagents/analytic tools; P.G., C.A.R., H.G., A.R.d.L., and W.B. analyzed data; and H.G., A.R.d.L., and W.B. wrote the paper.
↵ ^‖Present address: Eidgenössiche Technische Hochschule Zürich, Institut für Molekularbiologie und Biophysik, Eidgenössiche Technische Hochschule Hoenggerberg, 8093 Zürich, Switzerland.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 2P1T, 2P1U, and 2P1V).
This article contains supporting information online at www.pnas.org/cgi/content/full/0705356104/DC1.
Abbreviations:

RXR,

retinoid X receptor;

LBD,

ligand-binding domain;

NR,

nuclear receptor;

TIF2 NR2,

transcriptional intermediary factor 2 NR box 2;

ATRA,

all-trans retinoic acid;

APL,

acute promyelocytic leukemia;

RAR,

retinoic acid receptor.