22S-Butyl-1α,24R-dihydroxyvitamin D₃: Recovery of vitamin D receptor agonistic activity

We recently reported that 22S-butyl-1α,24R-dihydroxyvitamin D₃ 3 recovers the agonistic activity for vitamin D receptor (VDR), although its 25,26,27-trinor analog 2 is a potent VDR antagonist. To investigate the structural features involved in the recovery of agonism, we crystallized the ternary complex of VDR-ligand-binding domain, ligand 3 and coactivator peptide, and conducted X-ray crystallographic analysis of the complex. Compared with the complex with 2, the complex with 3 recovered the following structural features: a pincer-type hydrogen bond between the 24-hydroxyl group and VDR, the conformation of Leu305, the positioning of His301 and His393, the stability of the complex, and intimate hydrophobic interactions between the ligand and helix 12. In addition, we evaluated the potency of both compounds for recruiting RXR and coactivator. The results indicate that the complex with 3 generates a suitable surface for coactivator recruitment. These studies suggest that the action of 2 as an antagonist is caused by the generation of a surface not suitable for coactivator recruitment due to the lack of hydrophobic interactions with helix 12 as well as insufficient hydrogen bond formation between the 24-hydroxyl group and VDR. We concluded that the action of 3 as an agonist is based on the elimination of these structural defects in the complex with 2.