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Corepressor Excess Shifts the Two-Side Chain Vitamin D Analog Gemini from an Agonist to an Inverse Agonist of the Vitamin D Receptor

Departments of Biochemistry (M.M.G., P.S., C.C.) and Chemistry (M.P.), University of Kuopio, FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Professor Carsten Carlberg, Department of Biochemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: carlberg{at}messi.uku.fi.

The vitamin D receptor (VDR) is an endocrine nuclear receptor that binds with high affinity its natural ligand 1,25-dihydroxyvitamin D₃. Gemini is a 1,25-dihydroxyvitamin D₃ analog with two identical side chains that, despite its significantly increased volume, binds to the VDR and can function as a potent agonist. This study demonstrates that, at excess corepressor (CoR) levels, Gemini shifts from an agonist to an inverse agonist that actively recruits CoR proteins to the VDR and mediates superrepression. Under these conditions Gemini stabilizes the VDR into a silent conformation, in which helix 12 of the ligand-binding domain is repositioned and thus unable to contribute to coactivator interaction. Amino acid F422 has been described as the lock of helix 12 and seems to be the most critical VDR residue in the inverse agonistic action of Gemini. Molecular dynamics simulations of the Gemini-VDR complex support these observation by indicating that the second side chain of Gemini induces tension to the receptor structure that can be released by a shift of helix 12. Taken together, Gemini is the first described (conditional) inverse agonist to an endocrine nuclear receptor and may function as a sensor for the cell-specific coactivator/CoR ratio.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Coregulators:   NCOR

Ligands:   Calcitriol

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