Structural Characterization of the Interdomain Features of the Estrogen Receptor
Annual rept. 1 Mar 2008-28 Feb 2009
VIRGINIA UNIV CHARLOTTESVILLE
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The nuclear receptor NR superfamily in humans contains 48 distinct ligand-activated transcription factors in humans. These receptors rely on inter-connected functional domains to mediate their function in transcriptional regulation. The N-terminal AB domain of the NR family is poorly conserved in size and sequence. The DNA-binding domain DBD is highly conserved resides in the center of the polypeptide and binds to DNA response elements upstream of target genes. A hinge region connects the DBD to the ligand binding domain LBD. This region is not conserved in size or sequence. The LBD is responsible for binding to the hydrophobic ligands, consisting of steroids or dietary lipids, as well as to distinct coregulator proteins. The isolated DBDs and LBDs of the NR family have been studied by X-ray crystallography in many cases. However, the only existing 3-D structure of any intact nuclear receptor is that of the PPARRXR complex, which we published last year. In the case of the Estrogen Receptor ER-alpha, crystals structures are available for the LBD and DBD as single domains, and again unavailable with the intact protein. Therefore, there is no conceptual framework to help understand their domain-domain interactions and how these interactions shape the overall physiology and pharmacology of the Estrogen Receptor, including its response to drugs used for breast cancer, such as Tamoxifen . We are employing the first studies to crystallize full-length nuclear receptors including the ER-alpha , ideally in several different states with ER bound ligands as well as in a DNA complex with the estrogen response element.
- Medicine and Medical Research