PDBsum entry 2p1v

Hormone receptor

PDB id: 2p1v

Contents

Protein chain

211 a.a. *

Ligands

HIS-LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP

5TN

Waters ×74

* Residue conservation analysis

PDB id:

2p1v

Name:

Hormone receptor

Title:

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

Structure:

Retinoic acid receptor rxr-alpha. Chain: a. Fragment: ligand binding domain (residues 223-462). Synonym: retinoid x receptor alpha. Engineered: yes. Nuclear receptor coactivator 2 peptide. Chain: b. Fragment: nuclear receptor interaction motif 2 (residues 686-698). Synonym: ncoa-2, transcriptional intermediary factor 2.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rxra, nr2b1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence occurs naturally in humans. The peptide has been synthesized by automatic chemical synthesis.

Resolution:

2.20Å R-factor: 0.198 R-free: 0.232

Authors:

W.Bourguet,V.Nahoum

Key ref:

V.Nahoum et al. (2007). Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function. Proc Natl Acad Sci U S A, 104, 17323-17328. PubMed id: 17947383 DOI: 10.1073/pnas.0705356104

Date:

06-Mar-07 Release date: 09-Oct-07

Protein chain

P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha from Homo sapiens

Seq: 462 a.a.

Struc: 211 a.a.

DOI no: 10.1073/pnas.0705356104

Proc Natl Acad Sci U S A 104:17323-17328 (2007)

PubMed id: 17947383

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

V.Nahoum, E.Pérez, P.Germain, F.Rodríguez-Barrios, F.Manzo, S.Kammerer, G.Lemaire, O.Hirsch, C.A.Royer, H.Gronemeyer, A.R.de Lera, W.Bourguet.

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.

Selected figure(s)

Figure 1.
Fig. 1. Structures of the agonist CD3254 (compound 1) and of the series of alkyl ether analogs 2a–f.

Figure 4.
Fig. 4. Structures of RXR LBD in complex with partial agonists. (A) Overall structure of RXR LBD in complex with 2a, 2b, or 2c. The ligand is represented by red (oxygen atoms) and yellow (carbon atoms) van der Waals spheres. Helices and -strands are numbered from N to C terminus. Together, helices H3, H4, and H12 define the activation function 2 (AF-2) surface to which the TIF2 NR2 peptide is bound. (B) 2F[o]–F[c] density (1 ) for the LBP of RXR bound to 2b. W indicates a water molecule. (C) Closeup view showing the hydrogen bond network that stabilizes a water molecule in close proximity of L436. An identical hydrogen bond network is observed in the complex with 2a (not shown). (D) Superposition of the RXR LBP with 2b and 2c. (E) Comparison with the structure of RXR LBD bound to SR11237 (Protein Data Bank ID code 1MVC). To accommodate the particular features of 2a–c, L436 must adopt a conformation that differs from that found in the presence of the agonist. The dashed line between L436 and L455 indicates a short distance.

Figures were selected by an automated process.