1P8D

X-Ray Crystal Structure of LXR Ligand Binding Domain with 24(S),25-epoxycholesterol

Summary for 1P8D

• Entry DOI: 10.2210/pdb1p8d/pdb
• Descriptor: Oxysterols receptor LXR-beta, nuclear receptor coactivator 1 isoform 3, 17-[3-(3,3-DIMETHYL-OXIRANYL)-1-METHYL-PROPYL]-10,13-DIMETHYL-2,3,4,7,8,9,10,11,12,13,14,15,16,17-TETRADECAHYDRO-1H-CYC LOPENTA[A]PHENANTHREN-3-OL, ... (4 entities in total)
• Functional Keywords: lxr, epoxycholesterol, nuclear receptor, steroid receptor, liver x receptor, transcription, membrane protein-protein binding complex, membrane protein/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P55055
• Total number of polymer chains: 4
• Total formula weight: 63875.37

Authors

Williams, S.,Bledsoe, R.K.,Collins, J.L.,Boggs, S.,Lambert, M.H.,Miller, A.B.,Moore, J.,McKee, D.D.,Moore, L.,Nichols, J.,Parks, D.,Watson, M.,Wisely, B.,Willson, T.M. (deposition date: 2003-05-06, release date: 2003-07-08, Last modification date: 2024-04-03)

Primary citation

Williams, S.,Bledsoe, R.K.,Collins, J.L.,Boggs, S.,Lambert, M.H.,Miller, A.B.,Moore, J.,McKee, D.D.,Moore, L.,Nichols, J.,Parks, D.,Watson, M.,Wisely, B.,Willson, T.M.
X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch.
J.Biol.Chem., 278:27138-27143, 2003

PubMed Abstract: The x-ray crystal structures of the human liver X receptor beta ligand binding domain complexed to sterol and nonsterol agonists revealed a perpendicular histidinetryptophan switch that holds the receptor in its active conformation. Hydrogen bonding interactions with the ligand act to position the His-435 imidazole ring against the Trp-457 indole ring, allowing an electrostatic interaction that holds the AF2 helix in the active position. The neutral oxysterol 24(S),25-epoxycholesterol accepts a hydrogen bond from His-435 that positions the imidazole ring of the histidine above the pyrrole ring of the tryptophan. In contrast, the acidic T0901317 hydroxyl group makes a shorter hydrogen bond with His-435 that pulls the imidazole over the electron-rich benzene ring of the tryptophan, possibly strengthening the electrostatic interaction. Point mutagenesis of Trp-457 supports the observation that the ligand-histidine-tryptophan coupling is different between the two ligands. The lipophilic liver X receptor ligand-binding pocket is larger than the corresponding steroid hormone receptors, which allows T0901317 to adopt two distinct conformations. These results provide a molecular basis for liver X receptor activation by a wide range of endogenous neutral and acidic ligands.

PubMed: 12736258
DOI: 10.1074/jbc.M302260200

Experimental method

X-RAY DIFFRACTION (2.8 Å)