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 nucle ar receptor superfamily, forms dimers in solution that are probably st abilized by a dyad symmetrical interface formed by the ligand-binding domain. This receptor, however, recognizes DNA targets that are not dy ad 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 ringer region that confer selectivity for dir ect repeats with appropriate spacing. Reflecting the organization of t he DNA target, these regions, mapping to the tip of the first zinc fin ger module and the N and C termini of the second finger module, direct asymmetrical protein-protein contacts. A stereochemical model is prop osed for these interactions.