a The glucocorticoid receptor (GR) is the prototype of subfamily A, while the estrogen receptor (ER) is the prototype of subfamily B. For steroid receptors, the HRE regions are known to exist in one of three orientations: (i) direct repeats; (ii) inverted repeats; or (iii) everted repeat sequences; the repeat sequences are normally separated by 1 —» 6 (n) spacer nucleotides. Also, the HRE sequences actually present in the promoters of various hormone-regulated genes frequently display variation from the consensus HRE presented in this table. The consensus hormone responsive elements (HREs) are oriented 5' to 3', and the nonspecific "gap" nucleotide is denoted by n, followed by the second half-site. For the proximal and distal box regions of the receptor, the amino acids are represented by single-letter codes; amino acids that are highly conserved among species are capitalized. The discriminatory amino acids in the proximal region of the first zinc (see Figure 1-42) and in the distal region of the second zinc finger are marked with an asterisk. Reproduced from K. E. Lowe, A. Maiyar, and A. W. Norman "Vitamin-D Mediated Gene Expression," Critical Reviews in Eukaryo-tic Gene Expression 2(1), 65-109 (1992).

each receptor still displays very high specificity with regard to the specific genes modulated.

Within the DNA-binding domain of the receptor exist two so-called zinc fingers (see Figure 1-42). These zinc fingers form the principal interface between the DNA-binding domain of the receptor and the specific nucleotides of the HRE, which constitute the acceptor site (see Table 1-10). In a zinc finger domain, the Zn+ atom is coordinated to four amino acid side chains, usually two histidine and two cysteine residues. In the primary structure for the Zn+ finger motif, the two fingers are separated from one another by approximately 12 amino acid residues. Figure 1-42C illustrates the subtle but important differences in the Zn+ finger of the HRE of the glucocorticoid receptor versus that of the estrogen receptor. There are examples of single amino acid mutations that generate a crippled or totally inactive receptor. Thus, in the l,25(OH)2D3 receptor,

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