Differential use of transcription activation function 2 domain of the vitamin D receptor by 1,25-dihydroxyvitamin D3 and its A ring-modified analogs

Molecular Endocrinology
S PelegG H Posner

Abstract

Analogs of 1,25-dihydroxyvitamin D3 (1,25D3) can be used to elucidate details of vitamin D receptor (VDR) activation. The A ring-modified analog, (TN-2) has 15-fold less affinity for VDR, but its transcriptional activity is diminished 1000-fold. Likewise, the ability of TN-2 to induce a protease-resistant conformation in VDR is 1/1000 that of 1,25D3. The stability of the VDR-TN-2 complexes is also significantly lower than VDR-1,25D3 complexes. Mapping the VDR-binding site of TN-2 showed that it had a significantly greater requirement for transcription activation function 2 (AF-2) residues than 1,25D3 did. These results suggest that the increased requirement for AF-2 residues that was induced by the A ring modifications is associated with diminished receptor activation. To determine whether restoring the potency of TN-2 by additional structural modifications would change the requirements for AF-2 residues, we synthesized hybrid analogs with 1beta-hydroxymethyl-3-epi groups and with dimethyl groups at positions 26 and 27 of the side chain, without or with a double bond between CD ring positions 16 and 17. We found that the side chain modification enhanced transcriptional activity 150-fold, increased the ability of the receptor to...Continue Reading

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Citations

Jan 16, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Gary H PosnerSara Peleg
May 14, 2008·Clinica Chimica Acta; International Journal of Clinical Chemistry·Indra Ramasamy
Aug 31, 2002·Advances in Renal Replacement Therapy·J Wesley PikeNirupama K Shevde
Apr 24, 2001·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·L VerlindenR Bouillon
Mar 7, 2000·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·A VerstuyfR Bouillon
Feb 3, 2007·European Journal of Immunology·Evelyne van EttenChantal Mathieu
Jun 16, 2011·Endocrinology·Sylvia Christakos, Hector F DeLuca
Dec 30, 1999·Endocrinology·D FeldmanA V Krishnan
Jun 26, 1999·The Journal of Biological Chemistry·A Racz, J Barsony

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