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Crystal Structure of the Human Liver X Receptor b Ligand-binding Domain in Complex with a Synthetic Agonist



Crystal Structure of the Human Liver X Receptor b Ligand-binding Domain in Complex with a Synthetic Agonist



Journal of Molecular Biology 334(5): 3-61



LXRb 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 LXRb by agonists activates a number of genes that are involved in the regulation of lipid metabolism and cholesterol efflux from cells. Therefore, LXRb may represent a novel therapeutic target for the treatment of dyslipidemia and atherosclerosis. Here, we report the X-ray crystal structure of the LXRb 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. Reprinted by permission of the publisher.

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