Vincent Laudet, Hinrich Gronemeyer, in The Nuclear Receptor FactsBook, 2002 DNA binding Extensive chromosome folding will be required in order to exert an influence on transcription. It is noteworthy that nuclear-receptor binding sites are found in typical promoter regions, upstream and nearby the transcription start site, but a significant number are located in intragenic regions at distances above 25,000 base pairs (25 kb). Further specificity may come from binding of the modulating region to upstream or downstream DNA sequences (return to Figure 8-6(b)). Note that the DBD of RXR is always situated upstream (5′) of its partner. The RXR–PPAR dimer preferably recognizes DR1, the RXR–RAR recognizes DR2 or DR5, and the dimer RXR–VDR preferably recognizes DR3. The thyroid hormone-receptor homodimer (THR–THR) or heterodimer (RXR–THR) recognizes DR4. Each additional base pair separates the half-sites by 3.4 Å and introduces a relative rotation of 36°. Because the DNA sequence of the direct repeat is similar for all nuclear receptors concerned, a measure of discrimination is provided by varying the spacer length.
For the two inverted-repeat sequences the spacer number is always three (termed IR3), whereas for the direct repeats the number of spacers varies from 1 to 5 (termed DR1–DR5). All half-sites are separated by a number of base pairs. We distinguish two main types: binding of homodimers to inverted repeats, such as the steroid-hormone receptors, and binding of homo- or heterodimers (with RXR) to direct-repeat sites, such as the thyroid-hormone receptor, the retinoic-acid receptor, the vitamin D3 receptor, and peroxisome proliferation-activating receptor ( Figure 8-8). The DNA-binding sites, response elements, consist of two half-sites, each of six base pairs.