1upw: Difference between revisions

Revision as of 16:27, 21 February 2008

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 as ligand. Known structural/functional Site: . 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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OCA

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 ==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 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.
+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==
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 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Budzinski, R.M.]]
+[[Category: Budzinski, R M.]]
 [[Category: Heckel, A.]]
 [[Category: Hoerer, S.]]
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 [[Category: transcription factor]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:03:48 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:27:10 2008''