1s0x
From Proteopedia
(New page: 200px<br /> <applet load="1s0x" size="450" color="white" frame="true" align="right" spinBox="true" caption="1s0x, resolution 2.20Å" /> '''Crystal structure o...) |
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| - | [[Image:1s0x.gif|left|200px]]<br /> | + | [[Image:1s0x.gif|left|200px]]<br /><applet load="1s0x" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1s0x" size=" | + | |
caption="1s0x, resolution 2.20Å" /> | caption="1s0x, resolution 2.20Å" /> | ||
'''Crystal structure of the human RORalpha ligand binding domain in complex with cholesterol sulfate at 2.2A'''<br /> | '''Crystal structure of the human RORalpha ligand binding domain in complex with cholesterol sulfate at 2.2A'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The retinoic acid-related orphan receptor alpha (RORalpha) is an orphan | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1S0X is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with C3S as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1S0X is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=C3S:'>C3S</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S0X OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Fournier, B.]] | [[Category: Fournier, B.]] | ||
[[Category: Kallen, J.]] | [[Category: Kallen, J.]] | ||
| - | [[Category: Schlaeppi, J | + | [[Category: Schlaeppi, J M.]] |
[[Category: C3S]] | [[Category: C3S]] | ||
[[Category: ligand binding domain]] | [[Category: ligand binding domain]] | ||
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[[Category: three-layered alpha helical sandwich]] | [[Category: three-layered alpha helical sandwich]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:56:43 2008'' |
Revision as of 12:56, 21 February 2008
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Crystal structure of the human RORalpha ligand binding domain in complex with cholesterol sulfate at 2.2A
Overview
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.
About this Structure
1S0X is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
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
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