Ligand recognition by the vitamin D receptor

Three-dimensional structure of the ligand binding domain (LBD) of the vitam in D receptor (VDR) docked with the natural ligand 1 alpha ,25-dihydroxyvit amin D-3 [1,25-(OH)(2)D-3] has been mostly solved by the X-ray crystallogra phic analysis of the deletion mutant (VDR-LBD Delta 165-215). The important focus, from now on. is how the VDR recognizes and interacts with potent sy nthetic ligands. We now report the docking models of the VDR with three fun ctionally and structurally interesting ligands, 22-oxa-1.25-(OH)(2)D-3 (OCT ), 20-epi-1,25-(OH)(2)D-3 and 20-epi-22-oxa-24,26,27-trihomo-1.25-(OH)(2)D- 3. In parallel with the computational docking studies, we prepared twelve o ne-point mutants of amino acid residues lining the ligand binding pocket of the VDR and examined their transactivation potency induced by 1125-(OH)(2) D-3 and these synthetic ligands. The results indicate that L233, R274, W286 , H397 and Y401 are essential for holding the all ligands tested, S278 and Q400 are not important at all, and the importance of S237, V234, S275, C288 and H305 is variable depending on the side-chain structure of the ligands. Based on these studies, we suggested key structural factors to bestow the selective action on OCT and the augmented activities on 20-epi-ligands. Fur thermore, the docking models coincided well with our proposed active space- region theory of vitamin D based on the conformational analyses of ligands. (C) 2001 Elsevier Science Ltd. All rights reserved.