2P1V

Crystal structure of the ligand binding domain of the retinoid X receptor alpha in complex with 3-(2'-propoxy)-tetrahydronaphtyl cinnamic acid and a fragment of the coactivator TIF-2

Summary for 2P1V

• Entry DOI: 10.2210/pdb2p1v/pdb
• Related: 1FBY 1LBD 1MVC 1XDK 2p1t 2p1u
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2 peptide, (2E)-3-[4-HYDROXY-3-(5,5,8,8-TETRAMETHYL-3-PROPOXY-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL)PHENYL]ACRYLIC ACID, ... (4 entities in total)
• Functional Keywords: protein-ligand complex, hormone receptor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P19793 Q15596
• Total number of polymer chains: 2
• Total formula weight: 28844.43

Authors

Bourguet, W.,Nahoum, V. (deposition date: 2007-03-06, release date: 2007-10-09, Last modification date: 2023-08-30)

Primary citation

Nahoum, V.,Perez, E.,Germain, P.,Rodriguez-Barrios, F.,Manzo, F.,Kammerer, S.,Lemaire, G.,Hirsch, O.,Royer, C.A.,Gronemeyer, H.,de Lera, A.R.,Bourguet, W.
Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function.
Proc.Natl.Acad.Sci.Usa, 104:17323-17328, 2007

PubMed Abstract: Retinoid X receptors (RXRalpha, -beta, and -gamma) 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.

PubMed: 17947383
DOI: 10.1073/pnas.0705356104

Experimental method

X-RAY DIFFRACTION (2.2 Å)