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FIGURE 13-16 Schematic representation of the two forms of the progesterone receptor protein, PRa and PRB. The amino acid sequences of PRA and PRB are identical except that PRA lacks the first 165 amino acids present on the amino terminus of PRB. The domain regions are similar to that described in Figure 1-26. Modified from Graham, J. D., Yeates, C., Balleine, R. L., Harvey, S. S., Milliken, J. S., Bilous, A. M., and Clarke, C. L. (1996). Progesterone receptor A and B protein expression in human breast cancer. ]. Steroid Biochem. Mol. Biol. 56, 93-98.

change in the receptor protein. The experimental evidence supporting this conclusion included the use of protease digestion and monoclonal antibody mapping to detect changes in the receptor-ligand complex. It was argued that if a ligand induced a different conformation in the receptor, various protease digestion sites would become more or less sensitive to digestion, depending upon their location in the receptor. The consequence of the ligand-induced conformational change is that the receptor becomes activated and competent to form a functional transcription complex on the promoter of a gene. In contrast (see Figure 13-20B), when an antagonist binds to a receptor, either no conformational change or a different conformational change occurs, which does not yield a normally activated receptor; accordingly, the receptor-ligand complex cannot generate a functional transcription complex.

One example of a clinically useful progestational antagonist is the use of RU-486 as an agent to interfere with normal PR actions, with the consequence that, in early pregnancy, an abortion will occur. Several lines of evidence have indicated that RU-486 induces unique conformations of the PR different from that mediated by progesterone.

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