title: X-ray structures of the LXRalpha LBD in its homodimeric form and implications for heterodimer signaling.
abstract: Liver X receptors (LXRs) are nuclear receptors that are central regulators of cholesterol homeostasis, and synthetic LXR agonists have shown promise as promoters of reverse cholesterol transport and anti-inflammatory agents. Here, we present three X-ray structures of three different agonists bound to the ligand binding domain of LXRalpha. These compounds are GW3965, F(3)methylAA, and a benzisoxazole urea, and we show that these diverse chemical scaffolds address common structural themes, leading to high binding affinity for LXR. Our structures show the LXRalpha ligand binding domain in its homodimeric form, an arrangement previously thought to be stereochemically difficult. A comparison with existing structures of the LXRbeta homodimer and LXRalpha:RXR (retinoid X receptor) heterodimers explains differences in dimer affinity and leads us to propose a model for allosteric activation in nuclear receptor dimers, in which an unactivated RXR partner provides an inhibitory tail wrap to the cofactor binding pocket of LXR.
authors.affiliation: Department of Chemistry, Merck Research Labs, Newhouse, ML1 5SH, Scotland, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fradera
authors.forename: Diep
authors.initials: D
authors.lastname: Vu
authors.forename: Olaf
authors.initials: O
authors.lastname: Nimz
authors.forename: Robert
authors.initials: R
authors.lastname: Skene
authors.forename: David
authors.initials: D
authors.lastname: Hosfield
authors.forename: Robert
authors.initials: R
authors.lastname: Wynands
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cooke
authors.forename: Anders
authors.initials: A
authors.lastname: Haunsø
authors.forename: Angela
authors.initials: A
authors.lastname: King
authors.forename: D Jonathan
authors.initials: DJ
authors.lastname: Bennett
authors.forename: Ross
authors.initials: R
authors.lastname: McGuire
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Uitdehaag
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000378:metabolism; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors / Q000737:chemistry* / Q000378:metabolism; D010648:Phenylacetates / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: C460362:3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benzisoxazolyl)propylthio)phenylacetic acid; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D007555:Isoxazoles; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates; D013844:Thiazoles; C466948:benzisothiazole