Atomic structure of progesterone complexed with its receptor.
The physiological effects of progestins are mediated by the progesterone receptor, a member of the steroid/nuclear receptor superfamily. As progesterone is required for maintenance of pregnancy, its receptor has been a target for pharmaceuticals. Here we report the 1.8 A crystal structure of a progesterone-bound ligand-binding domain of the human progesterone receptor. The nature of this structure explains the receptor's selective affinity for progestins and establishes a common mode of recognition of 3-oxy steroids by the cognate receptors. Although the overall fold of the progesterone receptor is similar to that found in related receptors, the progesterone receptor has a quite different mode of dimerization. A hormone-induced stabilization of the carboxy-terminal secondary structure of the ligand-binding domain of the progesterone receptor accounts for the stereochemistry of this distinctive dimer, explains the receptor's characteristic pattern of ligand-dependent protease resistance and its loss of repression, and indicates how the anti-progestin RU486 might work in birth control. The structure also indicates that the analogous 3-keto-steroid receptors may have a similar mechanism of action.
Williams
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SP
Department of Molecular Biophysics and Biochemistry, and the Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06510, USA.
Sigler
P B
PB
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D015735:Mifepristone / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D011980:Receptors, Progesterone / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000737:chemistry
D006727:Hormone Antagonists; D008024:Ligands; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D015735:Mifepristone; D011374:Progesterone