1skx
From Proteopedia
(New page: 200px<br /> <applet load="1skx" size="450" color="white" frame="true" align="right" spinBox="true" caption="1skx, resolution 2.8Å" /> '''Structural Disorder ...) |
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| - | [[Image:1skx.gif|left|200px]]<br /> | + | [[Image:1skx.gif|left|200px]]<br /><applet load="1skx" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1skx" size=" | + | |
caption="1skx, resolution 2.8Å" /> | caption="1skx, resolution 2.8Å" /> | ||
'''Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin'''<br /> | '''Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The human nuclear xenobiotic receptor, pregnane X receptor (PXR), detects | + | The human nuclear xenobiotic receptor, pregnane X receptor (PXR), detects a variety of structurally distinct endogenous and xenobiotic compounds and controls expression of genes central to drug and cholesterol metabolism. The macrolide antibiotic rifampicin, a front-line treatment for tuberculosis, is an established PXR agonist and, at 823 Da, is one of the largest known ligands for the receptor. We present the 2.8 A crystal structure of the ligand-binding domain of human PXR in complex with rifampicin. We also use structural and mutagenesis data to examine the origins of the directed promiscuity exhibited by the PXRs across species. Three structurally flexible loops adjacent to the ligand-binding pocket of PXR are disordered in this crystal structure, including the 200-210 region that is part of a sequence insert novel to the promiscuous PXRs relative to other members of the nuclear receptor superfamily. The 4-methyl-1-piperazinyl ring of rifampicin, which would lie adjacent to the disordered protein regions, is also disordered and not observed in the structure. Taken together, our results indicate that one wall of the PXR ligand-binding cavity can remain flexible even when the receptor is in complex with an activating ligand. These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1SKX 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 RFP as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1SKX 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=RFP:'>RFP</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SKX OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Chrencik, J | + | [[Category: Chrencik, J E.]] |
| - | [[Category: Orans, J | + | [[Category: Orans, J O.]] |
| - | [[Category: Redinbo, M | + | [[Category: Redinbo, M R.]] |
[[Category: Xue, Y.]] | [[Category: Xue, Y.]] | ||
[[Category: RFP]] | [[Category: RFP]] | ||
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[[Category: rifampicin]] | [[Category: rifampicin]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:02:34 2008'' |
Revision as of 13:02, 21 February 2008
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Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin
Contents |
Overview
The human nuclear xenobiotic receptor, pregnane X receptor (PXR), detects a variety of structurally distinct endogenous and xenobiotic compounds and controls expression of genes central to drug and cholesterol metabolism. The macrolide antibiotic rifampicin, a front-line treatment for tuberculosis, is an established PXR agonist and, at 823 Da, is one of the largest known ligands for the receptor. We present the 2.8 A crystal structure of the ligand-binding domain of human PXR in complex with rifampicin. We also use structural and mutagenesis data to examine the origins of the directed promiscuity exhibited by the PXRs across species. Three structurally flexible loops adjacent to the ligand-binding pocket of PXR are disordered in this crystal structure, including the 200-210 region that is part of a sequence insert novel to the promiscuous PXRs relative to other members of the nuclear receptor superfamily. The 4-methyl-1-piperazinyl ring of rifampicin, which would lie adjacent to the disordered protein regions, is also disordered and not observed in the structure. Taken together, our results indicate that one wall of the PXR ligand-binding cavity can remain flexible even when the receptor is in complex with an activating ligand. These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics.
Disease
Known diseases associated with this structure: Adrenoleukodystrophy, neonatal OMIM:[600414], Zellweger syndrome OMIM:[600414]
About this Structure
1SKX is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin., Chrencik JE, Orans J, Moore LB, Xue Y, Peng L, Collins JL, Wisely GB, Lambert MH, Kliewer SA, Redinbo MR, Mol Endocrinol. 2005 May;19(5):1125-34. Epub 2005 Feb 10. PMID:15705662
Page seeded by OCA on Thu Feb 21 15:02:34 2008
