PDBsum entry 1n83

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Lipid binding protein PDB id
Protein chain
251 a.a. *
Waters ×419
* Residue conservation analysis
PDB id:
Name: Lipid binding protein
Title: Crystal structure of the complex between the orphan nuclear hormone receptor ror(alpha)-lbd and cholesterol
Structure: Nuclear receptor ror-alpha. Chain: a. Fragment: ligand binding domain, residues 304-556. Synonym: nuclear receptor rzr-alpha. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
1.63Å     R-factor:   0.202     R-free:   0.223
Authors: J.A.Kallen,J.M.Schlaeppi,F.Bitsch,S.Geisse,M.Geiser, I.Delhon,B.Fournier
Key ref:
J.A.Kallen et al. (2002). X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure, 10, 1697-1707. PubMed id: 12467577 DOI: 10.1016/S0969-2126(02)00912-7
19-Nov-02     Release date:   11-Dec-02    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P35398  (RORA_HUMAN) -  Nuclear receptor ROR-alpha
523 a.a.
251 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 10 residue positions (black crosses)

 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: 10.1016/S0969-2126(02)00912-7 Structure 10:1697-1707 (2002)
PubMed id: 12467577  
X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha.
J.A.Kallen, J.M.Schlaeppi, F.Bitsch, S.Geisse, M.Geiser, I.Delhon, B.Fournier.
The retinoic acid-related orphan receptor alpha (RORalpha) is an orphan member of the subfamily 1 of nuclear hormone receptors. No X-ray structure of RORalpha has been described so far, and no ligand has been identified. We describe the first crystal structure of the ligand binding domain (LBD) of RORalpha, at 1.63 A resolution. This structure revealed a ligand present in the ligand binding pocket (LBP), which was identified by X-ray crystallography as cholest-5-en-3beta-ol (cholesterol). Moreover, RORalpha transcriptional activity could be modulated by changes in intracellular cholesterol level or mutation of residues involved in cholesterol binding. These findings suggest that RORalpha could play a key role in the regulation of cholesterol homeostasis and thus represents an important drug target in cholesterol-related diseases.
  Selected figure(s)  
Figure 3.
Figure 3. Exchange of Cholesterol with Cholesterol Sulfate Detected by Mass SpectrometryCholesterol sulfate was dissolved at 50 mM in DMSO and added at 2.5 mM final concentration to the (His)[6]RORa LBD[270-523] solution at 135 M. The resulting solution was incubated overnight at 37C. A control experiment was done by incubating the same amount of RORa LBD protein with 5% DMSO under identical conditions. MaxEnt deconvoluted mass spectrum of (His)[6]RORa-LBD[270-523] (top) and (His)[6]RORa LBD[270-523] with cholesterol sulfate (bottom). The protein concentration was approximately 15 M in 50 mM AcONH[4] (pH 7.0). The spectra were recorded under identical conditions with Vc = 20 volts.
  The above figure is reprinted by permission from Cell Press: Structure (2002, 10, 1697-1707) copyright 2002.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23007570 M.Veldhoen, and V.Brucklacher-Waldert (2012).
Dietary influences on intestinal immunity.
  Nat Rev Immunol, 12, 696-708.  
19786043 A.C.Silveira, M.A.Morrison, F.Ji, H.Xu, J.B.Reinecke, S.M.Adams, T.M.Arneberg, M.Janssian, J.E.Lee, Y.Yuan, D.A.Schaumberg, M.G.Kotoula, E.E.Tsironi, A.N.Tsiloulis, D.Z.Chatzoulis, J.W.Miller, I.K.Kim, G.S.Hageman, L.A.Farrer, N.B.Haider, and M.M.DeAngelis (2010).
Convergence of linkage, gene expression and association data demonstrates the influence of the RAR-related orphan receptor alpha (RORA) gene on neovascular AMD: a systems biology based approach.
  Vision Res, 50, 698-715.  
20453923 D.N.Langelaan, and J.K.Rainey (2010).
Membrane catalysis of peptide-receptor binding.
  Biochem Cell Biol, 88, 203-210.  
20463884 J.Montagne, C.Lecerf, J.P.Parvy, J.M.Bennion, T.Radimerski, M.L.Ruhf, F.Zilbermann, N.Vouilloz, H.Stocker, E.Hafen, S.C.Kozma, and G.Thomas (2010).
The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila.
  PLoS Genet, 6, e1000937.  
20463469 L.A.Solt, P.R.Griffin, and T.P.Burris (2010).
Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics.
  Curr Opin Lipidol, 21, 204-211.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
20659512 L.Xiao, X.Xie, and Y.Zhai (2010).
Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism.
  Adv Drug Deliv Rev, 62, 1316-1321.  
19887649 N.Kumar, L.A.Solt, J.J.Conkright, Y.Wang, M.A.Istrate, S.A.Busby, R.D.Garcia-Ordonez, T.P.Burris, and P.R.Griffin (2010).
The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist.
  Mol Pharmacol, 77, 228-236.  
  19381306 A.M.Jetten (2009).
Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.
  Nucl Recept Signal, 7, e003.  
19161383 K.L.Furber, M.A.Churchward, T.P.Rogasevskaia, and J.R.Coorssen (2009).
Identifying critical components of native Ca2+-triggered membrane fusion. Integrating studies of proteins and lipids.
  Ann N Y Acad Sci, 1152, 121-134.  
19680455 M.Runge-Morris, and T.A.Kocarek (2009).
Regulation of Sulfotransferase and UDP-Glucuronosyltransferase Gene Expression by the PPARs.
  PPAR Res, 2009, 728941.  
19811676 N.Garcia-Reyero, I.R.Adelman, D.Martinovic, L.Liu, and N.D.Denslow (2009).
Site-specific impacts on gene expression and behavior in fathead minnows (Pimephales promelas) exposed in situ to streams adjacent to sewage treatment plants.
  BMC Bioinformatics, 10, S11.  
19778719 T.Hirota, and S.A.Kay (2009).
High-throughput screening and chemical biology: new approaches for understanding circadian clock mechanisms.
  Chem Biol, 16, 921-927.  
19440305 X.Yuan, T.C.Ta, M.Lin, J.R.Evans, Y.Dong, E.Bolotin, M.A.Sherman, B.M.Forman, and F.M.Sladek (2009).
Identification of an endogenous ligand bound to a native orphan nuclear receptor.
  PLoS ONE, 4, e5609.  
19164466 Y.Chen, S.Coulter, A.M.Jetten, and J.A.Goldstein (2009).
Identification of human CYP2C8 as a retinoid-related orphan nuclear receptor target gene.
  J Pharmacol Exp Ther, 329, 192-201.  
18005000 E.Duplus, C.Gras, V.Soubeyre, G.Vodjdani, Y.Lemaigre-Dubreuil, and B.Brugg (2008).
Phosphorylation and transcriptional activity regulation of retinoid-related orphan receptor alpha 1 by protein kinases C.
  J Neurochem, 104, 1321-1332.  
18441015 P.Lau, R.L.Fitzsimmons, S.Raichur, S.C.Wang, A.Lechtken, and G.E.Muscat (2008).
The orphan nuclear receptor, RORalpha, regulates gene expression that controls lipid metabolism: staggerer (SG/SG) mice are resistant to diet-induced obesity.
  J Biol Chem, 283, 18411-18421.  
18535165 T.Wada, H.S.Kang, A.M.Jetten, and W.Xie (2008).
The emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation.
  Exp Biol Med (Maywood), 233, 1191-1201.  
17374568 M.V.Flores, C.Hall, A.Jury, K.Crosier, and P.Crosier (2007).
The zebrafish retinoid-related orphan receptor (ror) gene family.
  Gene Expr Patterns, 7, 535-543.  
17635184 V.Dias, and V.Ribeiro (2007).
The expression of the solute carriers NTCP and OCT-1 is regulated by cholesterol in HepG2 cells.
  Fundam Clin Pharmacol, 21, 445-450.  
17532527 Y.Shi (2007).
Orphan nuclear receptors in drug discovery.
  Drug Discov Today, 12, 440-445.  
18418469 A.M.Jetten, and J.H.Joo (2006).
Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development.
  Adv Dev Biol, 16, 313-355.  
16539693 F.Boukhtouche, G.Vodjdani, C.I.Jarvis, J.Bakouche, B.Staels, J.Mallet, J.Mariani, Y.Lemaigre-Dubreuil, and B.Brugg (2006).
Human retinoic acid receptor-related orphan receptor alpha1 overexpression protects neurones against oxidative stress-induced apoptosis.
  J Neurochem, 96, 1778-1789.  
16555296 F.Frédéric, C.Chianale, C.Oliver, and J.Mariani (2006).
Enhanced endocrine response to novel environment stress and lack of corticosterone circadian rhythm in staggerer (Rora sg/sg) mutant mice.
  J Neurosci Res, 83, 1525-1532.  
16741567 S.N.Ramakrishnan, and G.E.Muscat (2006).
The orphan Rev-erb nuclear receptors: a link between metabolism, circadian rhythm and inflammation?
  Nucl Recept Signal, 4, e009.  
15888456 F.Molnár, M.Matilainen, and C.Carlberg (2005).
Structural determinants of the agonist-independent association of human peroxisome proliferator-activated receptors with coactivators.
  J Biol Chem, 280, 26543-26556.  
15707893 I.N.Krylova, E.P.Sablin, J.Moore, R.X.Xu, G.M.Waitt, J.A.MacKay, D.Juzumiene, J.M.Bynum, K.Madauss, V.Montana, L.Lebedeva, M.Suzawa, J.D.Williams, S.P.Williams, R.K.Guy, J.W.Thornton, R.J.Fletterick, T.M.Willson, and H.A.Ingraham (2005).
Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1.
  Cell, 120, 343-355.
PDB codes: 1ymt 1yok 1yow
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.  
15803199 K.King-Jones, and C.S.Thummel (2005).
Nuclear receptors--a perspective from Drosophila.
  Nat Rev Genet, 6, 311-323.  
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
15821743 M.Akashi, and T.Takumi (2005).
The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1.
  Nat Struct Mol Biol, 12, 441-448.  
16054837 T.Balla (2005).
Found in the crystal: phospholipid ligands for nuclear orphan receptors.
  Trends Endocrinol Metab, 16, 289-290.  
15246430 G.Benoit, M.Malewicz, and T.Perlmann (2004).
Digging deep into the pockets of orphan nuclear receptors: insights from structural studies.
  Trends Cell Biol, 14, 369-376.  
14722075 J.Kallen, J.M.Schlaeppi, F.Bitsch, I.Delhon, and B.Fournier (2004).
Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A.
  J Biol Chem, 279, 14033-14038.
PDB code: 1s0x
14982928 K.Duda, Y.I.Chi, and S.E.Shoelson (2004).
Structural basis for HNF-4alpha activation by ligand and coactivator binding.
  J Biol Chem, 279, 23311-23316.
PDB code: 1pzl
15610735 R.X.Xu, M.H.Lambert, B.B.Wisely, E.N.Warren, E.E.Weinert, G.M.Waitt, J.D.Williams, J.L.Collins, L.B.Moore, T.M.Willson, and J.T.Moore (2004).
A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer.
  Mol Cell, 16, 919-928.
PDB codes: 1xv9 1xvp
15606784 S.Sanglier, W.Bourguet, P.Germain, V.Chavant, D.Moras, H.Gronemeyer, N.Potier, and A.Van Dorsselaer (2004).
Monitoring ligand-mediated nuclear receptor-coregulator interactions by noncovalent mass spectrometry.
  Eur J Biochem, 271, 4958-4967.  
14570920 A.N.Moraitis, and V.Giguère (2003).
The co-repressor hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation.
  J Biol Chem, 278, 52511-52518.  
12958591 C.Stehlin-Gaon, D.Willmann, D.Zeyer, S.Sanglier, A.Van Dorsselaer, J.P.Renaud, D.Moras, and R.Schüle (2003).
All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta.
  Nat Struct Biol, 10, 820-825.
PDB codes: 1n4h 1nq7
12820970 E.P.Sablin, I.N.Krylova, R.J.Fletterick, and H.A.Ingraham (2003).
Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1.
  Mol Cell, 11, 1575-1585.
PDB code: 1pk5
14498828 F.M.Sladek (2003).
Nuclear receptors as drug targets: new developments in coregulators, orphan receptors and major therapeutic areas.
  Expert Opin Ther Targets, 7, 679-684.  
12969312 G.Eberl, and D.R.Littman (2003).
The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches.
  Immunol Rev, 195, 81-90.  
12923182 K.A.Lee, H.Fuda, Y.C.Lee, M.Negishi, C.A.Strott, and L.C.Pedersen (2003).
Crystal structure of human cholesterol sulfotransferase (SULT2B1b) in the presence of pregnenolone and 3'-phosphoadenosine 5'-phosphate. Rationale for specificity differences between prototypical SULT2A1 and the SULT2BG1 isoforms.
  J Biol Chem, 278, 44593-44599.
PDB codes: 1q1q 1q1z 1q20 1q22
16604183 S.Laitinen, and B.Staels (2003).
Potential roles of ROR-alpha in cardiovascular endocrinology.
  Nucl Recept Signal, 1, e011.  
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.