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J. Biol. Chem., Vol. 281, Issue 15, 10516-10526, April 14, 2006

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Vitamin D Receptor Agonists Specifically Modulate the Volume of the Ligand-binding Pocket^*

Ferdinand Molnár, Mikael Peräkylä, and Carsten Carlberg¹

From the Department of Biochemistry and the Department of Chemistry, University of Kuopio, FIN-70211 Kuopio, Finland

Existing crystal structure data has indicated that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂ D₃) and its analogues bind the ligand-binding pocket (LBP) of the human vitamin D receptor in a very similar fashion. Because docking of a ligand into the LBP is a more flexible process than crystallography can monitor, we analyzed 1,25(OH)₂D₃, its 20-epi derivative MC1288, the two side-chain analogues Gemini and Ro43-83582 (a hexafluoro-derivative) by molecular dynamics simulations in a complex with the vitamin D receptor ligand-binding domain and a co-activator peptide. Superimposition of the structures showed that the side chain of MC1288, the first side chain of the conformation II of Gemini, the second side chain of Ro43-83582 in conformation I and the first side chain of Ro43-83582 in conformation II take the same agonistic position as the side chain of 1,25(OH)₂D₃. Compared with the LBP of the natural hormone MC1288 reduced the volume by 17%, and Gemini expanded it by 19%. The shrinking of the LBP of MC1288 and its expansion to accommodate the second side chain of Gemini or Ro43-83582 is the combined result of minor movements of more than 30 residues and major movements of a few critical amino acids. The agonist-selective recognition of anchoring OH groups by the conformational flexible residues Ala-303, Leu-309, and His-397 was confirmed by in vitro assays. In summary, variations in the volume of agonists lead to adaptations in the volume of the LBP and alternative contacts of anchoring OH-groups.

Received for publication, December 21, 2005 , and in revised form, February 6, 2006.

^* This work was supported by The Academy of Finland, the Finnish Cancer Organization, and the Kuopio University Pharmacy Fund (to C. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and Fig. S3.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, University of Kuopio, P.O. box 1627, FIN-70211 Kuopio, Finland. Tel.: 358-17-163062; Fax: 358-17-2811510; E-mail: carlberg{at}messi.uku.fi.

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