spacer
spacer

PDBsum entry 2p1t

Go to PDB code: 
protein ligands links
Hormone receptor PDB id
2p1t
Jmol
Contents
Protein chain
211 a.a. *
Ligands
HIS-LYS-ILE-LEU-
HIS-ARG-LEU-LEU-
GLN-ASP
3TN
Waters ×112
* Residue conservation analysis
PDB id:
2p1t
Name: Hormone receptor
Title: Crystal structure of the ligand binding domain of the retinoid x receptor alpha in complex with 3-(2'-methoxy)- 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).
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
Resolution:
1.80Å     R-factor:   0.198     R-free:   0.218
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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha
Seq:
Struc:
462 a.a.
211 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     4 terms  

 

 
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21364553 R.Patani, A.J.Hollins, T.M.Wishart, C.A.Puddifoot, S.Alvarez, A.R.de Lera, D.J.Wyllie, D.A.Compston, R.A.Pedersen, T.H.Gillingwater, G.E.Hardingham, N.D.Allen, and S.Chandran (2011).
Retinoid-independent motor neurogenesis from human embryonic stem cells reveals a medial columnar ground state.
  Nat Commun, 2, 214.  
20543827 A.le Maire, C.Teyssier, C.Erb, M.Grimaldi, S.Alvarez, A.R.de Lera, P.Balaguer, H.Gronemeyer, C.A.Royer, P.Germain, and W.Bourguet (2010).
A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor.
  Nat Struct Mol Biol, 17, 801-807.
PDB codes: 3kmr 3kmz
20063036 A.le Maire, W.Bourguet, and P.Balaguer (2010).
A structural view of nuclear hormone receptor: endocrine disruptor interactions.
  Cell Mol Life Sci, 67, 1219-1237.
PDB code: 3kwy
20056921 T.Blom, N.Bäck, A.L.Mutka, R.Bittman, Z.Li, A.de Lera, P.T.Kovanen, U.Diczfalusy, and E.Ikonen (2010).
FTY720 stimulates 27-hydroxycholesterol production and confers atheroprotective effects in human primary macrophages.
  Circ Res, 106, 720-729.  
21152046 Y.Sato, N.Ramalanjaona, T.Huet, N.Potier, J.Osz, P.Antony, C.Peluso-Iltis, P.Poussin-Courmontagne, E.Ennifar, Y.Mély, A.Dejaegere, D.Moras, and N.Rochel (2010).
The "Phantom Effect" of the Rexinoid LG100754: structural and functional insights.
  PLoS One, 5, e15119.
PDB code: 3a9e
19270714 A.le Maire, M.Grimaldi, D.Roecklin, S.Dagnino, V.Vivat-Hannah, P.Balaguer, and W.Bourguet (2009).
Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors.
  EMBO Rep, 10, 367-373.
PDB code: 3e94
19791803 C.E.Wagner, P.W.Jurutka, P.A.Marshall, T.L.Groy, A.van der Vaart, J.W.Ziller, J.K.Furmick, M.E.Graeber, E.Matro, B.V.Miguel, I.T.Tran, J.Kwon, J.N.Tedeschi, S.Moosavi, A.Danishyar, J.S.Philp, R.O.Khamees, J.N.Jackson, D.K.Grupe, S.L.Badshah, and J.W.Hart (2009).
Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).
  J Med Chem, 52, 5950-5966.  
19757405 J.Lu, M.I.Dawson, Q.Y.Hu, Z.Xia, J.D.Dambacher, M.Ye, X.K.Zhang, and E.Li (2009).
The effect of antagonists on the conformational exchange of the retinoid X receptor alpha ligand-binding domain.
  Magn Reson Chem, 47, 1071-1080.  
19216008 S.Pérez-Rodríguez, M.A.Ortiz, R.Pereira, F.Rodríguez-Barrios, A.R.de Lera, and F.J.Piedrafita (2009).
Highly twisted adamantyl arotinoids: synthesis, antiproliferative effects and RXR transactivation profiles.
  Eur J Med Chem, 44, 2434-2446.  
19496083 W.P.Lippert, C.Burschka, K.Götz, M.Kaupp, D.Ivanova, C.Gaudon, Y.Sato, P.Antony, N.Rochel, D.Moras, H.Gronemeyer, and R.Tacke (2009).
Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology.
  ChemMedChem, 4, 1143-1152.
PDB codes: 2zxz 2zy0
  18607089 V.Nahoum, A.Lipski, F.Quillard, J.F.Guichou, Y.Boublik, E.Pérez, P.Germain, A.R.de Lera, and W.Bourguet (2008).
Nuclear receptor ligand-binding domains: reduction of helix H12 dynamics to favour crystallization.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 614-616.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.