Discovery of ligands that modulate the pocket structure of vitamin D receptor

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To develop vitamin D receptor ligands which separate the various biological activities of 1a,25-dihydroxyvitamin D3, we focused on the structure of ligand-binding pocket of the receptor, especially the variable part of the pocket. As a result, we discovered vitamin D analogues with a branched side chain that induce structural rearrangement of the amino acid residues lining the ligand-binding pocket. These analogs showed agonistic, partial agonistic or antagonistic activities. By X-ray analysis, we found one of partial agonists exists in two conformations, namely agonist and antagonist conformations, in a single crystal.