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.