1nrl: Difference between revisions
New page: left|200px<br /> <applet load="1nrl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nrl, resolution 2.00Å" /> '''Crystal Structure o... |
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[[Image:1nrl.gif|left|200px]]<br /> | [[Image:1nrl.gif|left|200px]]<br /><applet load="1nrl" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1nrl, resolution 2.00Å" /> | caption="1nrl, resolution 2.00Å" /> | ||
'''Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813'''<br /> | '''Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813'''<br /> | ||
==Overview== | ==Overview== | ||
The pregnane X receptor (PXR) detects the presence of a wide variety of | The pregnane X receptor (PXR) detects the presence of a wide variety of endogenous and xenobiotic compounds, and is a master regulator of the expression of genes central to drug metabolism and excretion. We present the 2.0A crystal structure of the human PXR ligand-binding domain (LBD) in complex with the cholesterol-lowering compound SR12813 and a 25 amino acid residue fragment of the human steroid receptor coactivator-1 (SRC-1) containing one LXXLL motif. PXR crystallizes as a homodimer in the asymmetric unit in this structure and possesses a novel alpha2 helix adjacent to its ligand-binding cavity. The SRC-1 peptide forms two distinct helices and binds adjacent to the ligand-dependent transactivation AF-2 helix on the surface of PXR. In contrast with previous PXR structures, in which SR12813 bound in multiple orientations, the small SR12813 agonist in this structure binds in a single, unique orientation within the receptor's ligand-binding pocket and contacts the AF-2 helix. Thermal denaturation studies reveal that the SR12813 ligand and SRC-1 coactivator peptide each stabilize the LBD of PXR, and that together they exert an additive effect on the stability of the receptor. These results indicate that the binding of coactivator to the surface of PXR limits the ability of this promiscuous receptor to "breathe" and helps to trap a single, active conformation of SR12813. They further reveal that specificity is required for PXR activation. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1NRL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SRL as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 1NRL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SRL:'>SRL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NRL OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Davis-Searles, P | [[Category: Davis-Searles, P R.]] | ||
[[Category: Lambert, M | [[Category: Lambert, M H.]] | ||
[[Category: Redinbo, M | [[Category: Redinbo, M R.]] | ||
[[Category: Watkins, R | [[Category: Watkins, R E.]] | ||
[[Category: SRL]] | [[Category: SRL]] | ||
[[Category: coactivator]] | [[Category: coactivator]] | ||
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[[Category: xenobiotic]] | [[Category: xenobiotic]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:09:17 2008'' | ||
Revision as of 12:09, 21 February 2008
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Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813
Overview
The pregnane X receptor (PXR) detects the presence of a wide variety of endogenous and xenobiotic compounds, and is a master regulator of the expression of genes central to drug metabolism and excretion. We present the 2.0A crystal structure of the human PXR ligand-binding domain (LBD) in complex with the cholesterol-lowering compound SR12813 and a 25 amino acid residue fragment of the human steroid receptor coactivator-1 (SRC-1) containing one LXXLL motif. PXR crystallizes as a homodimer in the asymmetric unit in this structure and possesses a novel alpha2 helix adjacent to its ligand-binding cavity. The SRC-1 peptide forms two distinct helices and binds adjacent to the ligand-dependent transactivation AF-2 helix on the surface of PXR. In contrast with previous PXR structures, in which SR12813 bound in multiple orientations, the small SR12813 agonist in this structure binds in a single, unique orientation within the receptor's ligand-binding pocket and contacts the AF-2 helix. Thermal denaturation studies reveal that the SR12813 ligand and SRC-1 coactivator peptide each stabilize the LBD of PXR, and that together they exert an additive effect on the stability of the receptor. These results indicate that the binding of coactivator to the surface of PXR limits the ability of this promiscuous receptor to "breathe" and helps to trap a single, active conformation of SR12813. They further reveal that specificity is required for PXR activation.
Disease
Known diseases associated with this structure: Adrenoleukodystrophy, neonatal OMIM:[600414], Zellweger syndrome OMIM:[600414]
About this Structure
1NRL is a Protein complex structure of sequences from Homo sapiens with SRL as ligand. Full crystallographic information is available from OCA.
Reference
Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor., Watkins RE, Davis-Searles PR, Lambert MH, Redinbo MR, J Mol Biol. 2003 Aug 22;331(4):815-28. PMID:12909012
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