![]() Vitamin D, a seco-steroid hormone (steroid with an opened B-ring) is active only in the metabolized form 1α,25-dihydroxyvitamin D3. Based on the present data, the explanation of the superagonist effect is to be found in higher stability and longer half-life of the active complex, thereby excluding different conformations of the ligand binding domain. KH1060 compensates this energy cost by additional contacts. The ligands exhibit a low-energy conformation for MC1288 and a more strained conformation for the two others. The inverted geometry of the C20 methyl group induces different paths of the aliphatic chains. Differences are observed only for the 17β-aliphatic chains that adapt their conformation to anchor the 25-hydroxyl group to His-305 and His-397. In all complexes, the A- to D-ring moieties of the ligands adopt the same conformation and form identical contacts with the protein. The crystal structures of the ligand-binding domain (LBD) of the vitamin D receptor complexed to 1α,25(OH) 2D 3 and the 20-epi analogs, MC1288 and KH1060, show that the protein conformation is identical, conferring a general character to the observation first made for retinoic acid receptor (RAR) that, for a given LBD, the agonist conformation is unique, the ligands adapting to the binding pocket. ![]()
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December 2022
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