1upw: Difference between revisions
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==Overview== | ==Overview== | ||
LXRbeta belongs to the nuclear hormone receptor superfamily of, ligand-activated transcription factors. Its natural ligands are supposed, to be oxidised derivatives of cholesterol. Stimulation of LXRbeta by, agonists activates a number of genes that are involved in the regulation, of lipid metabolism and cholesterol efflux from cells. Therefore, LXRbeta, may represent a novel therapeutic target for the treatment of dyslipidemia, and atherosclerosis.Here, we report the X-ray crystal structure of the, LXRbeta ligand-binding domain in complex with a synthetic agonist, T-0901317. This compound occupies the ligand-binding pocket of the, receptor, forms numerous lipophilic contacts with the protein and one, crucial hydrogen bond to His435 and stabilises the agonist conformation of, the receptor ... | LXRbeta belongs to the nuclear hormone receptor superfamily of, ligand-activated transcription factors. Its natural ligands are supposed, to be oxidised derivatives of cholesterol. Stimulation of LXRbeta by, agonists activates a number of genes that are involved in the regulation, of lipid metabolism and cholesterol efflux from cells. Therefore, LXRbeta, may represent a novel therapeutic target for the treatment of dyslipidemia, and atherosclerosis.Here, we report the X-ray crystal structure of the, LXRbeta ligand-binding domain in complex with a synthetic agonist, T-0901317. This compound occupies the ligand-binding pocket of the, receptor, forms numerous lipophilic contacts with the protein and one, crucial hydrogen bond to His435 and stabilises the agonist conformation of, the receptor ligand-binding domain. The recruitment of the AF2-region of, the protein is not achieved via direct polar interactions of the ligand, with protein side-chains of this helical segment, but rather via few, hydrophobic contacts and probably more importantly via indirect effects, involving the pre-orientation of side-chains that surround the, ligand-binding pocket and form the interface to the AF2-helix.On the basis, of these results we propose a binding mode and a mechanism of action for, the putative natural ligands, oxidised derivatives of cholesterol. | ||
==About this Structure== | ==About this Structure== | ||
1UPW is a | 1UPW 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 444 as [http://en.wikipedia.org/wiki/ligand ligand]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1UPW OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transcription factor]] | [[Category: transcription factor]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:38:42 2007'' | ||
Revision as of 15:33, 5 November 2007
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CRYSTAL STRUCTURE OF THE HUMAN LIVER X RECEPTOR BETA LIGAND BINDING DOMAIN IN COMPLEX WITH A SYNTHETIC AGONIST
OverviewOverview
LXRbeta belongs to the nuclear hormone receptor superfamily of, ligand-activated transcription factors. Its natural ligands are supposed, to be oxidised derivatives of cholesterol. Stimulation of LXRbeta by, agonists activates a number of genes that are involved in the regulation, of lipid metabolism and cholesterol efflux from cells. Therefore, LXRbeta, may represent a novel therapeutic target for the treatment of dyslipidemia, and atherosclerosis.Here, we report the X-ray crystal structure of the, LXRbeta ligand-binding domain in complex with a synthetic agonist, T-0901317. This compound occupies the ligand-binding pocket of the, receptor, forms numerous lipophilic contacts with the protein and one, crucial hydrogen bond to His435 and stabilises the agonist conformation of, the receptor ligand-binding domain. The recruitment of the AF2-region of, the protein is not achieved via direct polar interactions of the ligand, with protein side-chains of this helical segment, but rather via few, hydrophobic contacts and probably more importantly via indirect effects, involving the pre-orientation of side-chains that surround the, ligand-binding pocket and form the interface to the AF2-helix.On the basis, of these results we propose a binding mode and a mechanism of action for, the putative natural ligands, oxidised derivatives of cholesterol.
About this StructureAbout this Structure
1UPW is a Single protein structure of sequence from Homo sapiens with 444 as ligand. Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist., Hoerer S, Schmid A, Heckel A, Budzinski RM, Nar H, J Mol Biol. 2003 Dec 12;334(5):853-61. PMID:14643652
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