Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain

The ligand binding domain of the human vitamin D receptor (VDR) was modeled based on the crystal structure of the retinoic acid receptor. The ligand b inding pocket of our VDR model is spacious at the helix 11 site and confine d at the beta-turn site. The ligand 1 alpha,25-dihydroxyvitamin D-3 was ass umed to be anchored in the ligand binding pocket with its side chain headin g to helix 11 (site 2) and the A-ring toward the beta-turn (site 1). Three residues forming hydrogen bonds with the functionally important 1 alpha- an d 25-hydroxyl groups of 1 alpha,25-dihydroxyvitamin D-3 were identified and confirmed by mutational analysis: the 1 alpha-hydroxyl group is forming pi ncer-type hydrogen bonds with S237 and R274 and the 25-hydroxyl group is in teracting with H397. Docking potential for various ligands to the VDR model was examined, and the results are in good agreement with our previous thre e-dimensional structure-function theory.