1s0x

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the human RORalpha ligand binding domain in complex with cholesterol sulfate at 2.2A

Structural highlights

1s0x is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RORA_HUMAN Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence. This isomer binds to the consensus sequence 5'-[AT][TA]A[AT][CGT]TAGGTCA-3'. Regulates a number of genes involved in lipid metabolism such as apolipoproteins AI, APOA5, CIII, CYP71 and PPARgamma, in cerebellum and photoreceptor development including PCP2, OPN1SW, OPN1SM AND ARR3, in circadian rhythm with BMAL1, and skeletal muscle development with MYOD1. Possible receptor for cholesterol or one of its derivatives.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The retinoic acid-related orphan receptor alpha (RORalpha) is an orphan member of the subfamily 1 of nuclear hormone receptors. Our recent structural and functional studies have led to the hypothesis that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. We have now solved the x-ray crystal structure of the ligand binding domain of RORalpha in complex with cholesterol-3-O-sulfate following a ligand exchange experiment. In contrast to the 3-hydroxyl of cholesterol, the 3-O-sulfate group makes additional direct hydrogen bonds with three residues of the RORalpha ligand binding domain, namely NH-Gln(289), NH-Tyr(290), and NH1-Arg(370). When compared with the complex with cholesterol, seven well ordered water molecules have been displaced, and the ligand is slightly shifted toward the hydrophilic part of the ligand binding pocket, which is ideally suited for interactions with a sulfate group. These additional ligand-protein interactions result in an increased affinity of cholesterol sulfate when compared with cholesterol, as shown by mass spectrometry analysis done under native conditions and differential scanning calorimetry. Moreover, mutational studies show that the higher binding affinity of cholesterol sulfate translates into an increased transcriptional activity of RORalpha. Our findings suggest that cholesterol sulfate could play a crucial role in the regulation of RORalpha in vivo.

Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A.,Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B J Biol Chem. 2004 Apr 2;279(14):14033-8. Epub 2004 Jan 13. PMID:14722075^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lau P, Bailey P, Dowhan DH, Muscat GE. Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD. Nucleic Acids Res. 1999 Jan 15;27(2):411-20. PMID:9862959
↑ Sundvold H, Lien S. Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem Biophys Res Commun. 2001 Sep 21;287(2):383-90. PMID:11554739 doi:http://dx.doi.org/10.1006/bbrc.2001.5602
↑ Raspe E, Duez H, Gervois P, Fievet C, Fruchart JC, Besnard S, Mariani J, Tedgui A, Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha. J Biol Chem. 2001 Jan 26;276(4):2865-71. Epub 2000 Oct 26. PMID:11053433 doi:http://dx.doi.org/10.1074/jbc.M004982200
↑ Moraitis AN, Giguere V. The co-repressor hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation. J Biol Chem. 2003 Dec 26;278(52):52511-8. Epub 2003 Oct 21. PMID:14570920 doi:http://dx.doi.org/10.1074/jbc.M308152200
↑ Genoux A, Dehondt H, Helleboid-Chapman A, Duhem C, Hum DW, Martin G, Pennacchio LA, Staels B, Fruchart-Najib J, Fruchart JC. Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORalpha. Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1186-92. Epub 2005 Mar 24. PMID:15790933 doi:http://dx.doi.org/10.1161/01.ATV.0000163841.85333.83
↑ Lind U, Nilsson T, McPheat J, Stromstedt PE, Bamberg K, Balendran C, Kang D. Identification of the human ApoAV gene as a novel RORalpha target gene. Biochem Biophys Res Commun. 2005 Apr 29;330(1):233-41. PMID:15781255 doi:http://dx.doi.org/10.1016/j.bbrc.2005.02.151
↑ Lechtken A, Hornig M, Werz O, Corvey N, Zundorf I, Dingermann T, Brandes R, Steinhilber D. Extracellular signal-regulated kinase-2 phosphorylates RORalpha4 in vitro. Biochem Biophys Res Commun. 2007 Jul 6;358(3):890-6. Epub 2007 May 11. PMID:17512500 doi:http://dx.doi.org/10.1016/j.bbrc.2007.05.016
↑ Kim EJ, Yoo YG, Yang WK, Lim YS, Na TY, Lee IK, Lee MO. Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling. Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1796-802. doi:, 10.1161/ATVBAHA.108.171546. Epub 2008 Jul 24. PMID:18658046 doi:http://dx.doi.org/10.1161/ATVBAHA.108.171546
↑ Duplus E, Gras C, Soubeyre V, Vodjdani G, Lemaigre-Dubreuil Y, Brugg B. Phosphorylation and transcriptional activity regulation of retinoid-related orphan receptor alpha 1 by protein kinases C. J Neurochem. 2008 Mar;104(5):1321-32. Epub 2007 Nov 10. PMID:18005000 doi:http://dx.doi.org/10.1111/j.1471-4159.2007.05074.x
↑ Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, Fournier B. 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. 2002 Dec;10(12):1697-707. PMID:12467577
↑ Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B. Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A. J Biol Chem. 2004 Apr 2;279(14):14033-8. Epub 2004 Jan 13. PMID:14722075 doi:10.1074/jbc.M400302200

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1s0x"

@@ Line 3: / Line 3: @@
 <StructureSection load='1s0x' size='340' side='right'caption='[[1s0x]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1s0x]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S0X OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1S0X FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1s0x]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S0X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1S0X FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C3S:CHOLEST-5-EN-3-YL+HYDROGEN+SULFATE'>C3S</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RORA, NR1F1, RZRA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C3S:CHOLEST-5-EN-3-YL+HYDROGEN+SULFATE'>C3S</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1s0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s0x OCA], [http://pdbe.org/1s0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1s0x RCSB], [http://www.ebi.ac.uk/pdbsum/1s0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1s0x ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1s0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s0x OCA], [https://pdbe.org/1s0x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1s0x RCSB], [https://www.ebi.ac.uk/pdbsum/1s0x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1s0x ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/RORA_HUMAN RORA_HUMAN]] Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence. This isomer binds to the consensus sequence 5'-[AT][TA]A[AT][CGT]TAGGTCA-3'. Regulates a number of genes involved in lipid metabolism such as apolipoproteins AI, APOA5, CIII, CYP71 and PPARgamma, in cerebellum and photoreceptor development including PCP2, OPN1SW, OPN1SM AND ARR3, in circadian rhythm with BMAL1, and skeletal muscle development with MYOD1. Possible receptor for cholesterol or one of its derivatives.<ref>PMID:9862959</ref> <ref>PMID:11554739</ref> <ref>PMID:11053433</ref> <ref>PMID:14570920</ref> <ref>PMID:15790933</ref> <ref>PMID:15781255</ref> <ref>PMID:17512500</ref> <ref>PMID:18658046</ref> <ref>PMID:18005000</ref> <ref>PMID:12467577</ref>
+[https://www.uniprot.org/uniprot/RORA_HUMAN RORA_HUMAN] Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence. This isomer binds to the consensus sequence 5'-[AT][TA]A[AT][CGT]TAGGTCA-3'. Regulates a number of genes involved in lipid metabolism such as apolipoproteins AI, APOA5, CIII, CYP71 and PPARgamma, in cerebellum and photoreceptor development including PCP2, OPN1SW, OPN1SM AND ARR3, in circadian rhythm with BMAL1, and skeletal muscle development with MYOD1. Possible receptor for cholesterol or one of its derivatives.<ref>PMID:9862959</ref> <ref>PMID:11554739</ref> <ref>PMID:11053433</ref> <ref>PMID:14570920</ref> <ref>PMID:15790933</ref> <ref>PMID:15781255</ref> <ref>PMID:17512500</ref> <ref>PMID:18658046</ref> <ref>PMID:18005000</ref> <ref>PMID:12467577</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 33: / Line 33: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bitsch, F]]
+[[Category: Bitsch F]]
-[[Category: Delhon, I]]
+[[Category: Delhon I]]
-[[Category: Fournier, B]]
+[[Category: Fournier B]]
-[[Category: Kallen, J]]
+[[Category: Kallen J]]
-[[Category: Schlaeppi, J M]]
+[[Category: Schlaeppi JM]]
-[[Category: Hormone-growth factor receptor complex]]
-[[Category: Ligand binding domain]]
-[[Category: Nuclear hormone receptor]]
-[[Category: Orphan receptor]]
-[[Category: Three-layered alpha helical sandwich]]

1s0x

From Proteopedia

Current revision

Crystal structure of the human RORalpha ligand binding domain in complex with cholesterol sulfate at 2.2A

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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