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: 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 demonstr

SUBMITTER: Bula CM 

PROVIDER: S-EPMC1920180 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature