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Crystallographic Comparison of the Estrogen and Progesterone Receptor's Ligand Binding Domains

David M. Tanenbaum, Yong Wang, Shawn P. Williams and Paul B. Sigler
Proceedings of the National Academy of Sciences of the United States of America
Vol. 95, No. 11 (May 26, 1998), pp. 5998-6003
Stable URL: http://www.jstor.org/stable/45320
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Crystallographic Comparison of the Estrogen and Progesterone Receptor's Ligand Binding Domains
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Abstract

The 2.8- angstrom crystal structure of the complex formed by estradiol and the human estrogen receptor-α ligand binding domain (hERα LBD) is described and compared with the recently reported structure of the progesterone complex of the human progesterone receptor ligand binding domain, as well as with similar structures of steroid/nuclear receptor LBDs solved elsewhere. The hormone-bound hERα LBD forms a distinctly different and probably more physiologically important dimer interface than its progesterone counterpart. A comparison of the specificity determinants of hormone binding reveals a common structural theme of mutually supported van der Waals and hydrogen-bonded interactions involving highly conserved residues. The previously suggested mechanism by which the estrogen receptor distinguishes estradiol's unique 3-hydroxy group from the 3-keto function of most other steroids is now described in atomic detail. Mapping of mutagenesis results points to a coactivator-binding surface that includes the region around the ``signature sequence'' as well as helix 12, where the ligand-dependent conformation of the activation function 2 core is similar in all previously solved steroid/nuclear receptor LBDs. A peculiar crystal packing event displaces helix 12 in the hERα LBD reported here, suggesting a higher degree of dynamic variability than expected for this critical substructure.

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