Development of Vitamin D Analogs Modulating the Pocket Structure of Vitamin D Receptor

Author(s): Keiko Yamamoto, Yasuaki Anami, Toshimasa Itoh

Journal Name: Current Topics in Medicinal Chemistry

Volume 14 , Issue 21 , 2014

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Graphical Abstract:


The first determination of the X-ray crystal structure of the ligand binding domain (LBD) of the vitamin D receptor (VDR) complexed with 1α,25-dihydroxyvitamin D3 was reported in 2000. Since then several dozen crystal structures of VDR accommodating various ligands have been presented. Almost all of these complexes display the canonical active conformation observed in the VDR-LBD/1α,25- dihydroxyvitamin D3 complex, and all have quite similar ligand binding pocket (LBP) architectures. To develop new VDR ligands as therapeutic agents, it is important to separate the various biological activities of 1α,25- dihydroxyvitamin D3, such as calcium regulation, cell differentiation and anti-proliferation, and immune modulation. We focused on the structure of the LBP and discovered that vitamin D analogs with a branched side chain induce structural rearrangement of the amino acid residues lining the LBP. These analogs formed an additional cavity in the LBP for accommodation of the side chain and thus altered the structure of the LBP. Interestingly, the ligands showed agonistic, partial agonistic, or antagonistic activity depending upon the structure of the side chain. These results indicate that ligands which alter the pocket structure open a new perspective for the development of VDR ligands exhibiting a specific biological activity.

Keywords: Butyl pocket, Pocket structure, Protein modulation, Receptor modulation, Vitamin D receptor.

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Article Details

Year: 2014
Published on: 23 December, 2014
Page: [2378 - 2387]
Pages: 10
DOI: 10.2174/156802661421141223091909
Price: $65

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