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Ligand-specific Structural Changes in the Vitamin D Receptor in Solution

Ligand-specific Structural Changes in the Vitamin D Receptor in Solution

Kiran K Singarapu, Jinge Zhu, Marco Tonelli, Hongyu Rao, Fariba M Assadi-Porter, William M Westler, Hector F DeLuca, John L Markley

Biochemistry. 2011 Dec 27;50(51):11025-33.

PMID: 22112050

Abstract:

Vitamin D receptor (VDR) is a member of the nuclear hormone receptor superfamily. When bound to a variety of vitamin D analogues, VDR manifests a wide diversity of physiological actions. The molecular mechanism by which different vitamin D analogues cause specific responses is not understood. The published crystallographic structures of the ligand binding domain of VDR (VDR-LBD) complexed with ligands that have differential biological activities have exhibited identical protein conformations. Here we report that rat VDR-LBD (rVDR-LBD) in solution exhibits differential chemical shifts when bound to three ligands that cause diverse responses: the natural hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)₂D₃], a potent agonist analogue, 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D₃ [2MD], and an antagonist, 2-methylene-(22E)-(24R)-25-carbobutoxy-26,27-cyclo-22-dehydro-1α,24-dihydroxy-19-norvitamin D₃ [OU-72]. Ligand-specific chemical shifts mapped not only to residues at or near the binding pocket but also to residues remote from the ligand binding site. The complexes of rVDR-LBD with native hormone and the potent agonist 2MD exhibited chemical shift differences in signals from helix-12, which is part of the AF2 transactivation domain that appears to play a role in the selective recruitment of coactivators. By contrast, formation of the complex of rVDR-LBD with the antagonist OU-72 led to disappearance of signals from residues in helices-11 and -12. We present evidence that disorder in this region of the receptor in the antagonist complex prevents the attachment of coactivators.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AS212673	1,25-Dihydroxyvitamin D3-13C3 (25,26,27-13C3) solution			Price
IAR42410579	(24R)-24,25-Dihydroxyvitamin D3 solution			Price

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