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This version published online on July 3, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0072
A more recent version of this article appeared on October 1, 2003
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Submitted on March 4, 2003
Accepted on June 26, 2003

Corepressor excess shifts the two side chain vitamin D analog Gemini from an agonist to an inverse agonist of the vitamin D receptor

Manuel Macias Gonzalez1, Petra Samenfeld1, Mikael Peräkylä1, and Carsten Carlberg1*

1 Departments of Biochemistryand Chemistry, University of Kuopio, FIN-70211 Kuopio, Finland

* To whom correspondence should be addressed. E-mail: carlberg{at}messi.uku.fi.

The vitamin D receptor (VDR) is an endocrine nuclear receptor (NR) that binds with high affinity its natural ligand 1{alpha},25-dihydroxyvitamin D3 (1{alpha}, 25(OH)2D3). Gemini is a 1{alpha},25(OH)2D3 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 super-repression. 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 (CoA) 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 NR and may function as a sensor for the cell-specific CoA/CoR ratio.
Key words: gene regulation • nuclear receptors • vitamin D receptor • corepressor • inverse agonist • receptor conformations • molecular dynamics simulation

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR
Coregulators:   NCOR
Ligands:   Calcitriol



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