Abstract
The molecular mechanism of action of the progesterone antagonist RU-486 is explained in terms of the known action of the progesterone receptor. RU-486 is a flat steroid molecule like progesterone but it also has a larger 11-beta aminophenyl substituent which apparently does not affect the affinity of binding of the antagonist to the receptor. RU-486 is the 1st antisteroid with an affinity higher than the natural hormone to be used clinically. The action of RU-486 is known in great detail because the molecular structure of the receptor and the DNA which it binds are defined. Unpredicted side effects due to extra-receptor activity have not been reported. The progesterone receptor contains a DNA binding domain (DBD) a ligand binding domain (LBD) to which progesterone attaches a positively charged hinge region that localizes docking in the nucleus and an N-terminal of unknown function presumably involved in gene activation. Normally the progesterone receptor (PR) is located in the nucleus. Before accepting the hormone it is thought to be protected by a heat-shock protein which is released after the receptor docks to the nucleus causing a conformational change in the shape of the PR. 2 PG molecules bind to a palindromic of the nucleus the hormone response element (HRE) forming a dimer. Since there are 2 types of PR these may be homo- or hetero-dimers. After this shape change transformation or expression of hormone-controlled genes occurs. With RU-486 binding to the nucleus occurs but the complex is stabilized so that little or no gene activation occurs. Indeed antagonist-receptor complexes behave differently on electrophoresis from native progesterone-PR complexes. Whether the putative transactivation function of the N-terminal of the receptor is affected is under investigation. In the absence of progesterone some agonist activity has been observed due to RU-486. Whether extra-nuclear effects such as down-regulation of the concentration of receptors are altered by RU-486 is unknown.
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