1skx
From Proteopedia
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[[Image:1skx.gif|left|200px]] | [[Image:1skx.gif|left|200px]] | ||
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'''Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin''' | '''Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin''' | ||
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[[Category: Redinbo, M R.]] | [[Category: Redinbo, M R.]] | ||
[[Category: Xue, Y.]] | [[Category: Xue, Y.]] | ||
| - | [[Category: | + | [[Category: Ligand binding domain]] |
| - | [[Category: | + | [[Category: Nuclear receptor]] |
| - | [[Category: | + | [[Category: Pregnane x receptor]] |
| - | [[Category: | + | [[Category: Rifampicin]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 08:49:50 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 05:49, 3 May 2008
Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin
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.
About this Structure
1SKX is a Single protein structure of sequence from Homo sapiens. 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 Sat May 3 08:49:50 2008
