期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 98, 期 10, 页码 5491-5496出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.091018698
关键词
20-epi analogs; nuclear receptors; VDR
The crystal structures of the ligand-binding domain (LBD) of the vitamin D receptor complexed to 1 alpha ,25(OH)(2)D-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 LED, the agonist conformation is unique, the ligands adapting to the binding pocket. In all complexes, the A- to D-ring moieties of the ligands adopt the same conformation and form identical contacts with the protein. Differences are observed only for the 17 beta -aliphatic chains that adapt their conformation to anchor the 25-hydroxyl group to His-305 and His-397. The inverted geometry of the C20 methyl group induces different paths of the aliphatic chains. The ligands exhibit a low-energy conformation for MC1288 and a more strained conformation for the two others. KH1060 compensates this energy cost by additional contacts. Based on the present data, the explanation of the superagonist effect is to he found in higher stability and longer half-life of the active complex, thereby excluding different conformations of the ligand binding domain.
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