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Atomic structure of progesterone complexed with its receptor

Abstract

The physiological effects of progestins are mediated by the progesterone receptor, a member of the steroid/nuclear receptor superfamily1. As progesterone is required for maintenance of pregnancy, its receptor has been a target for pharmaceuticals2. Here we report the 1.8 Å 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 receptors3,4,5,6, the progesterone receptor has a quite different mode of dimerization3,6. 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 repression7,8, 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.

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Figure 1: Comparison of the PR LBD with other LBDs.
Figure 2: The progesterone-binding pocket.
Figure 3: Comparison of the PR LBD and RXR LBD dimers.

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Acknowledgements

We thank M.-J. Tsai and B. O'Malley for the cDNA fragment containing the coding segment for the protein used here; C. Ogata (X4A-NSLS), L. Berman (X25-NSLS) and S. Ealick (CHESS) for access to and help with synchrotron radiation; R. Fletterick and D. Moras for useful structural information; D. Tanenbaum and Y.Wang for access to and discussions about their crystal structure of the oestradiol-ER-LBD complex; and members of P.B.S.'s laboratory for help with data collection. This work was supported in part by an NIH grant.

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Correspondence to Paul B. Sigler.

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Williams, S., Sigler, P. Atomic structure of progesterone complexed with its receptor. Nature 393, 392–396 (1998). https://doi.org/10.1038/30775

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