DNA target selectivity by the vitamin D3 receptor: mechanism of dimer binding to an asymmetric repeat element.

The 1,25-dihydroxyvitamin D3 receptor, like other members of the nuclear receptor superfamily, forms dimers in solution that are probably stabilized by a dyad symmetrical interface formed by the ligand-binding domain. This receptor, however, recognizes DNA targets that are not dyad symmetric but rather are organized as direct repeats of a hexameric sequence with a characteristic 3-bp spacing. Using molecular modeling and site-directed mutagenesis, we have identified regions within the vitamin D3 receptor zinc finger region that confer selectivity for direct repeats with appropriate spacing. Reflecting the organization of the DNA target, these regions, mapping to the tip of the first zinc finger module and the N and C termini of the second finger module, direct asymmetrical protein-protein contacts. A stereochemical model is proposed for these interactions.