The DNA binding domain is the most highly conserved feature of the superfamily. It is composed of two zinc binding modules, sometimes incorrectly referred to as zinc fingers. Because of a 2 amino acid insertion between the two zinc binding modules, the TR C domain consists of 68 amino acids instead of the much more typical 66. Otherwise, the TR contains all of the features common to the superfamily, including a number of invariant residues as well as a P box of the thyroid/retinoid/orphan class. This alpha-helical region at the C terminus of the first zinc binding module makes base specific contacts with the DNA binding site. The X-ray crystal structure of the DNA binding domain of TR has been determined as part of a TR-RXR-DNA co-crystal, by Evans and Sigler and coworkers (medline abstract). In this structure, a helix just C-terminal to the conventionally described DNA binding domain makes contact with the DNA in the 4 base pair spacer that separates the RXR and TR C domains in the complex. Such contacts may account for the ability of TRs to bind with high affinity to an octameric consensus that contains two conserved base pairs (TA) upstream of the hexameric consensus (AGGTCA) commonly recognized by the members of the thyroid/retinoid/orphan class (medline abstract).
Within the ligand binding domain there are at least three subregions that are conserved throughout the receptor superfamily. These conserved motifs have received various names, but in the context of the TRs the first two are frequently referred to as Tau(sub)i and the ninth heptad as described by Forman and Samuels (medline abstract. Tau(sub)i is near the N-terminus of the E domain, and corresponds to helices 2 and 3 in the recently described TRalpha crystal structure (medline abstract). The function of this motif is currently somewhat unclear, but it is thought to be involved in dimerization. The ninth heptad, which corresponds to a portion of helix 10 in the crystal structure, is more directly associated with dimerization in the TRs and in other superfamily members. The third motif is a short stretch that is at the C-terminus of the TRs. This region, referred to as AF-2, was originally described by Parker and coworkers (medline abstract) for the estrogen receptor and is required for the ligand dependent transcriptional activation by receptor superfamily members.
The region between the DNA and ligand binding domains is referred to as the hinge (D) domain, and has frequently been thought to serve only to link the two. However, this region is conserved in comparisons of TRalpha and TRbeta, and recent evidence from the Evans (medline abstract), Rosenfeld (medline abstract) and Glass medline abstract) laboratories suggests that it contains the binding site for trancriptional corepressor proteins that mediate the transcriptional repression function of unliganded receptors.
Except for a conserved 12 amino acid segment adjacent to the DNA binding domain, the N-terminal (A/B) domains of the TRs are completely divergent. This region is associated with transcriptional activation in other members of the receptor superfamily. There are reports that this is also the case for the TRs (medline abstract).