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

Citation:
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.
PDB ID: 2P1VDownload
MMDB ID: 59217
PDB Deposition Date: 2007/3/6
Updated in MMDB: 2007/11
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 2P1V: tetrameric; determined by author
Molecular Components in 2P1V
Label Count Molecule
Proteins (4 molecules)
2
Retinoic Acid Receptor Rxr-alpha(Gene symbol: RXRA)
Molecule annotation
2
Nuclear Receptor Coactivator 2 Peptide(Gene symbol: NCOA2)
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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