2o9i
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= NR1I2, PXR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= NR1I2, PXR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1skx|1SKX]], [[1nrl|1NRL]], [[1ilg|1ILG]], [[1ilh|1ILH]], [[1m13|1M13]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2o9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2o9i OCA], [http://www.ebi.ac.uk/pdbsum/2o9i PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2o9i RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
The human pregnane X receptor (PXR) recognizes a range of structurally and chemically distinct ligands and plays a key role in regulating the expression of protective gene products involved in the metabolism and excretion of potentially harmful compounds. The identification and development of PXR antagonists is desirable as a potential way to control the up-regulation of drug metabolism pathways during the therapeutic treatment of disease. We present the 2.8A resolution crystal structure of the PXR ligand binding domain (LBD) in complex with T0901317 (T1317), which is also an agonist of another member of the orphan class of the nuclear receptor superfamily, the liver X receptor (LXR). In spite of differences in the size and shape of the receptors' ligand binding pockets, key interactions with this ligand are conserved between human PXR and human LXR. Based on the PXR-T1317 structure, analogues of T1317 were generated with the goal of designing an PXR antagonist effective via the receptor's ligand binding pocket. We find that selectivity in activating PXR versus LXR was achieved; such compounds may be useful in addressing neurodegenerative diseases like Niemann-Pick C. We were not successful, however, in producing a PXR antagonist. Based on these observations, we conclude that the generation of PXR antagonists targeted to the ligand binding pocket may be difficult due to the promiscuity and structural conformability of this xenobiotic sensor. | The human pregnane X receptor (PXR) recognizes a range of structurally and chemically distinct ligands and plays a key role in regulating the expression of protective gene products involved in the metabolism and excretion of potentially harmful compounds. The identification and development of PXR antagonists is desirable as a potential way to control the up-regulation of drug metabolism pathways during the therapeutic treatment of disease. We present the 2.8A resolution crystal structure of the PXR ligand binding domain (LBD) in complex with T0901317 (T1317), which is also an agonist of another member of the orphan class of the nuclear receptor superfamily, the liver X receptor (LXR). In spite of differences in the size and shape of the receptors' ligand binding pockets, key interactions with this ligand are conserved between human PXR and human LXR. Based on the PXR-T1317 structure, analogues of T1317 were generated with the goal of designing an PXR antagonist effective via the receptor's ligand binding pocket. We find that selectivity in activating PXR versus LXR was achieved; such compounds may be useful in addressing neurodegenerative diseases like Niemann-Pick C. We were not successful, however, in producing a PXR antagonist. Based on these observations, we conclude that the generation of PXR antagonists targeted to the ligand binding pocket may be difficult due to the promiscuity and structural conformability of this xenobiotic sensor. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Adrenoleukodystrophy, neonatal OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600414 600414]], Zellweger syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600414 600414]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Redinbo, M R.]] | [[Category: Redinbo, M R.]] | ||
[[Category: Xue, Y.]] | [[Category: Xue, Y.]] | ||
| - | [[Category: 444]] | ||
[[Category: nuclear receptor]] | [[Category: nuclear receptor]] | ||
[[Category: pregnane x receptor]] | [[Category: pregnane x receptor]] | ||
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[[Category: t0901317]] | [[Category: t0901317]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:14:43 2008'' |
Revision as of 01:14, 31 March 2008
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| , resolution 2.80Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | NR1I2, PXR (Homo sapiens) | ||||||
| Related: | 1SKX, 1NRL, 1ILG, 1ILH, 1M13
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of the Human Pregnane X Receptor LBD in complex with an SRC-1 coactivator peptide and T0901317
Overview
The human pregnane X receptor (PXR) recognizes a range of structurally and chemically distinct ligands and plays a key role in regulating the expression of protective gene products involved in the metabolism and excretion of potentially harmful compounds. The identification and development of PXR antagonists is desirable as a potential way to control the up-regulation of drug metabolism pathways during the therapeutic treatment of disease. We present the 2.8A resolution crystal structure of the PXR ligand binding domain (LBD) in complex with T0901317 (T1317), which is also an agonist of another member of the orphan class of the nuclear receptor superfamily, the liver X receptor (LXR). In spite of differences in the size and shape of the receptors' ligand binding pockets, key interactions with this ligand are conserved between human PXR and human LXR. Based on the PXR-T1317 structure, analogues of T1317 were generated with the goal of designing an PXR antagonist effective via the receptor's ligand binding pocket. We find that selectivity in activating PXR versus LXR was achieved; such compounds may be useful in addressing neurodegenerative diseases like Niemann-Pick C. We were not successful, however, in producing a PXR antagonist. Based on these observations, we conclude that the generation of PXR antagonists targeted to the ligand binding pocket may be difficult due to the promiscuity and structural conformability of this xenobiotic sensor.
About this Structure
2O9I is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structure of the PXR-T1317 complex provides a scaffold to examine the potential for receptor antagonism., Xue Y, Chao E, Zuercher WJ, Willson TM, Collins JL, Redinbo MR, Bioorg Med Chem. 2007 Mar 1;15(5):2156-66. Epub 2006 Dec 20. PMID:17215127
Page seeded by OCA on Mon Mar 31 04:14:43 2008
