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PDBsum entry 1mzn

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protein ligands Protein-protein interface(s) links
Transcription PDB id
1mzn
Jmol
Contents
Protein chains
224 a.a. *
11 a.a. *
212 a.a. *
Ligands
BM6 ×4
Waters ×823
* Residue conservation analysis
PDB id:
1mzn
Name: Transcription
Title: Crystal structure at 1.9 angstroems resolution of the homodimer of human rxr alpha ligand binding domain bound to the synthetic agonist compound bms 649 and a coactivator peptide
Structure: Rxr retinoid x receptor. Chain: a, c, e, g. Fragment: ligand binding domain(residues 223-462). Synonym: retinoic acid receptor rxr-alpha. Engineered: yes. Nuclear receptor coactivator 2. Chain: b, d, f, h. Fragment: nr box. Synonym: grip1.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: chemical synthesis, this is the synthetic peptide fragment from grip-1 coactivator
Biol. unit: Tetramer (from PQS)
Resolution:
1.90Å     R-factor:   0.195     R-free:   0.232
Authors: P.F.Egea,A.Mitschler,D.Moras
Key ref: P.F.Egea et al. (2002). Molecular recognition of agonist ligands by RXRs. Mol Endocrinol, 16, 987-997. PubMed id: 11981034 DOI: 10.1210/mend.16.5.0823
Date:
09-Oct-02     Release date:   23-Oct-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha
Seq:
Struc:
462 a.a.
224 a.a.
Protein chains
Pfam   ArchSchema ?
Q15596  (NCOA2_HUMAN) -  Nuclear receptor coactivator 2
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1464 a.a.
11 a.a.
Protein chains
Pfam   ArchSchema ?
P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha
Seq:
Struc:
462 a.a.
212 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: 10.1210/mend.16.5.0823 Mol Endocrinol 16:987-997 (2002)
PubMed id: 11981034  
 
 
Molecular recognition of agonist ligands by RXRs.
P.F.Egea, A.Mitschler, D.Moras.
 
  ABSTRACT  
 
The nuclear receptor RXR is an obligate partner in many signal transduction pathways. We report the high-resolution structures of two complexes of the human RXRalpha ligand-binding domain specifically bound to two different and chemically unrelated agonist compounds: docosa hexaenoic acid, a natural derivative of eicosanoic acid, present in mammalian cells and recently identified as a potential endogenous RXR ligand in the mouse brain, and the synthetic ligand BMS 649. In both structures the RXR-ligand-binding domain forms homodimers and exhibits the active conformation previously observed with 9-cis-RA. Analysis of the differences in ligand-protein contacts (predominantly van der Waals forces) and binding cavity geometries and volumes for the several agonist-bound RXR structures clarifies the structural features important for ligand recognition. The L-shaped ligand-binding pocket adapts to the diverse ligands, especially at the level of residue N306, which might thus constitute a new target for drug-design. Despite its highest affinity 9-cis-RA displays the lowest number of ligand-protein contacts. These structural results support the idea that docosa hexaenoic acid and related fatty acids could be natural agonists of RXRs and question the real nature of the endogenous ligand(s) in mammalian cells.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
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
19004016 F.Borel, A.de Groot, C.Juillan-Binard, E.de Rosny, V.Laudet, E.Pebay-Peyroula, J.C.Fontecilla-Camps, and J.L.Ferrer (2009).
Crystal structure of the ligand-binding domain of the retinoid X receptor from the ascidian polyandrocarpa misakiensis.
  Proteins, 74, 538-542.
PDB code: 2q60
19845314 H.Fan, J.J.Irwin, B.M.Webb, G.Klebe, B.K.Shoichet, and A.Sali (2009).
Molecular docking screens using comparative models of proteins.
  J Chem Inf Model, 49, 2512-2527.  
19378296 M.I.Dawson, M.Ye, X.Cao, L.Farhana, Q.Y.Hu, Y.Zhao, L.P.Xu, A.Kiselyuk, R.G.Correa, L.Yang, T.Hou, J.C.Reed, P.Itkin-Ansari, F.Levine, M.F.Sanner, J.A.Fontana, and X.K.Zhang (2009).
Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene.
  ChemMedChem, 4, 1106-1119.  
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
19796154 Y.Nakagawa, and V.C.Henrich (2009).
Arthropod nuclear receptors and their role in molting.
  FEBS J, 276, 6128-6157.  
18088598 J.Lu, M.Chen, G.T.Dekoster, D.P.Cistola, and E.Li (2008).
The RXRalpha C-terminus T462 is a NMR sensor for coactivator peptide binding.
  Biochem Biophys Res Commun, 366, 932-937.  
18157857 K.Takamatsu, A.Takano, N.Yakushiji, K.Morishita, N.Matsuura, M.Makishima, H.I.Ali, E.Akaho, A.Tai, K.Sasaki, and H.Kakuta (2008).
Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRalpha-preferential agonist possessing a sulfonamide moiety.
  ChemMedChem, 3, 454-460.  
18297677 K.Takamatsu, A.Takano, N.Yakushiji, K.Morohashi, K.Morishita, N.Matsuura, M.Makishima, A.Tai, K.Sasaki, and H.Kakuta (2008).
The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRalpha/beta-dual agonist).
  ChemMedChem, 3, 780-787.  
18301758 L.M.Sanderson, P.J.de Groot, G.J.Hooiveld, A.Koppen, E.Kalkhoven, M.Müller, and S.Kersten (2008).
Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics.
  PLoS ONE, 3, e1681.  
18542946 N.Kumaresan, K.R.Sanjay, K.S.Venkatesh, R.K.Kadeppagari, G.Vijayalakshmi, and S.Umesh-Kumar (2008).
Partially saturated canthaxanthin purified from Aspergillus carbonarius induces apoptosis in prostrate cancer cell line.
  Appl Microbiol Biotechnol, 80, 467-473.  
18267129 S.Vibet, C.Goupille, P.Bougnoux, J.P.Steghens, J.Goré, and K.Mahéo (2008).
Sensitization by docosahexaenoic acid (DHA) of breast cancer cells to anthracyclines through loss of glutathione peroxidase (GPx1) response.
  Free Radic Biol Med, 44, 1483-1491.  
  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.  
17906643 A.R.de Lera, W.Bourguet, L.Altucci, and H.Gronemeyer (2007).
Design of selective nuclear receptor modulators: RAR and RXR as a case study.
  Nat Rev Drug Discov, 6, 811-820.  
17947383 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, and W.Bourguet (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.
PDB codes: 2p1t 2p1u 2p1v
17547694 Y.E.Liu, W.Pu, J.Wang, J.X.Kang, and Y.E.Shi (2007).
Activation of Stat5 and induction of a pregnancy-like mammary gland differentiation by eicosapentaenoic and docosapentaenoic omega-3 fatty acids.
  FEBS J, 274, 3351-3362.  
18850203 A.Bordoni, M.Di Nunzio, F.Danesi, and P.L.Biagi (2006).
Polyunsaturated fatty acids: From diet to binding to ppars and other nuclear receptors.
  Genes Nutr, 1, 95.  
16258897 J.Lengqvist, A.Mata de Urquiza, T.Perlmann, J.Sjövall, and W.J.Griffiths (2005).
Specificity of receptor-ligand interactions and their effect on dimerisation as observed by electrospray mass spectrometry: bile acids form stable adducts to the RXRalpha.
  J Mass Spectrom, 40, 1448-1461.  
16085421 J.Lengqvist, G.Alvélius, H.Jörnvall, J.Sjövall, T.Perlmann, and W.J.Griffiths (2005).
Electrospray mass spectrometry for the direct accurate mass measurement of ligands in complex with the retinoid X receptor alpha ligand binding domain.
  J Am Soc Mass Spectrom, 16, 1631-1640.  
15103326 A.IJpenberg, N.S.Tan, L.Gelman, S.Kersten, J.Seydoux, J.Xu, D.Metzger, L.Canaple, P.Chambon, W.Wahli, and B.Desvergne (2004).
In vivo activation of PPAR target genes by RXR homodimers.
  EMBO J, 23, 2083-2091.  
15178767 A.Luria, and J.D.Furlow (2004).
Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos.
  Proc Natl Acad Sci U S A, 101, 8987-8992.  
15373804 A.R.Barchuk, R.Maleszka, and Z.L.Simões (2004).
Apis mellifera ultraspiracle: cDNA sequence and rapid up-regulation by juvenile hormone.
  Insect Mol Biol, 13, 459-467.  
  15111325 C.L.Varley, J.Stahlschmidt, B.Smith, M.Stower, and J.Southgate (2004).
Activation of peroxisome proliferator-activated receptor-gamma reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells.
  Am J Pathol, 164, 1789-1798.  
15456909 L.J.Schwimmer, P.Rohatgi, B.Azizi, K.L.Seley, and D.F.Doyle (2004).
Creation and discovery of ligand-receptor pairs for transcriptional control with small molecules.
  Proc Natl Acad Sci U S A, 101, 14707-14712.  
15105832 Y.Brelivet, S.Kammerer, N.Rochel, O.Poch, and D.Moras (2004).
Signature of the oligomeric behaviour of nuclear receptors at the sequence and structural level.
  EMBO Rep, 5, 423-429.  
12745211 S.Sanglier, E.Leize, A.Van Dorsselaer, and F.Zal (2003).
Comparative ESI-MS study of approximately 2.2 MDa native hemocyanins from deep-sea and shore crabs: from protein oligomeric state to biotope.
  J Am Soc Mass Spectrom, 14, 419-429.  
12970175 S.Svensson, T.Ostberg, M.Jacobsson, C.Norström, K.Stefansson, D.Hallén, I.C.Johansson, K.Zachrisson, D.Ogg, and L.Jendeberg (2003).
Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation.
  EMBO J, 22, 4625-4633.
PDB code: 1uhl
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 code is shown on the right.