Induction of a novel conformation in the progesterone receptor by ZK299 involves a defined region of the carboxyl-terminal tail.

摘要: Progesterone receptor antagonists are a promising class of therapeutic drugs indicated for the treatment variety reproductive conditions. Understanding their mechanism action at molecular level is an important prerequisite development future generations these drugs. Using limited proteolytic analysis to monitor conformational changes in progesterone receptor, we can detect three distinct classes progestin antagonist. The effect first, RU486, on conformation carboxyl terminus has been previously described. second, exemplified by RWJ 47626, nonsteroidal compound with vitro antiprogestin activity, induces fragment pattern indistinguishable from that induced agonist R5020. Finally, ZK299 intermediate between R5020 and RU486. Site-directed mutagenesis carboxyl-terminal tail indicates region containing putative activation ...