Crystal Structure of the Vitamin D Receptor Ligand-Binding Domain with Lithocholic Acids

The secondary bile acid lithocholic acid (LCA) and its derivatives act as selective modulators of the vitamin D receptor (VDR), although their structures fundamentally differ from that of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). The complexes of the ligand-binding domain of rat VDR (VDR-LBD) with LCA and its derivatives revealed that the ligands bound to the same ligand-binding pocket (LBP) of VDR-LBD that 1,25(OH)2D3 binds to, but in the opposite orientation; their A-ring was positioned at the top of the LBP, whereas their acyclic tail was located at the bottom of the LBP. However, most of the hydrophobic and hydrophilic interactions observed in the complex with 1,25(OH)2D3 were reproduced in the complexes with LCA and its derivatives. Additional interactions between VDR-LBD and the C-3 substituents of the A-ring were also observed in the complexes, probably related to the observed difference in the potency among the LCA-type ligands. Recently, zebrafish VDR has been reported to have the second LBP on the outside of the canonical LBP, although its physiological function is unclear.