X-ray Crystal Structure of the Liver X Receptor β Ligand Binding Domain

Shawn Williams, Randy K. Bledsoe, Jon L. Collins, Sharon Boggs, Millard H. Lambert, Ann B. Miller, John Moore, David D. McKee, Linda Moore, Jason Nichols, Derek Parks, Mike Watson (+2 others)
2003 Journal of Biological Chemistry  
The x-ray crystal structures of the human liver X receptor ␤ 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
more » ... rogen 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.
doi:10.1074/jbc.m302260200 pmid:12736258 fatcat:4fva3fhqhjctdbgyxgjaecsgmu