Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects.

Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects. Research Abstract Details 

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Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects. Abstract Text:

Craig M Bula,June E Bishop,Anthony W Norman,

The positioning of helix 12 activation domain of nuclear receptor proteins is critically important for gene regulation. Perturbations of the helix 12 by larger analogs may alter interactions with transcriptional machinery which might give rise to selectivity. To explore the topology of the ligand binding pocket and how the bound ligand conceivably gives rise to altered transcriptional efficiencies, we have targeted 4 hydrophobic residues which contact the 25-carbon of the ligand, 1alpha,25(OH)(2)-vitamin D(3), and made a series of 13 mutants. Substitution of a smaller hydrophobic residue was poorly tolerated compared to a larger one for transactivation. The larger amino acids are likely better tolerated by promoting stronger Van der Waals forces with the ligand. Valine-418 mutants demonstrated an extreme example of this observation with mutation to leucine being transactivationally unaffected with alanine being the most affected of all single mutants. V418L resulted in a 1.3-fold increase in EC(50) for 1,25-D mediated transactivation whereas V418A resulted in a 53-fold increase when compared to wildtype VDR. Importantly, this difference is not explained by ligand binding data but by differential VDR protease sensitivity implying that V418L-VDR mutation assumes a better conformational interaction surface for coactivator than V418A. Importantly, the V418 location may accommodate larger sidechains and may even enhance the interaction with specific nuclear coactivators.

Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects. Publishing Authors By Initials

CM Bula,JE Bishop,AW Norman,

For similar genetic processes: gene expression regulation: trans-activation (genetics) research abstracts see: genetic processes: gene expression regulation: trans-activation (genetics) research

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Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of steroid biochemistry and molecular

VOLUME: 103

Page Numbers: 286-92

Journal Abbreviation: J. Steroid Biochem. Mol. Biol.

ISSN: 0960-0760

DAY: 3

MONTH: Mar

YEAR: 2007

Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9015483

Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects. Keywords Mesh Terms:

KEYWORDS: Trans-Activation (Genetics)

MESH TERMS: genetics

Chemical & Substance for Abstract: Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects. Information

Substance Name: Receptors, Calcitriol

Registry Number: 0

Grant and Affiliation Information for Conservative mutageneic perturbations of amino acids connecting helix 12 in the 1alpha,25(OH)2-D3 receptor (VDR) to the ligand cause significant transactivational effects.

AFFILIATION: Department of Biochemistry, University of California-Riverside, Riverside, CA 92521, USA.

Country: England

AGENCY: United States NIDDK

GRANT: DK 09012-30

ACRONYM: DK

MEDLINETA: J Steroid Biochem Mol Biol

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