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Structure/Function of Recombinant Human Estrogen Receptor

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Annual rept. 1 Sep 97-31 Aug 98

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Interaction of the estrogen receptor with its ligands is mediated by a C-terminal region of the protein designated the hormone binding domain HBD. We initiated structure-function studies in an attempt to improve our understanding of how estrogen activates the receptor and how antagonists inhibit its activity. We previously reported high yield expression of recombinant human estrogen receptor HBD, and our results suggest that the isolated HBD forms dimers in solution and undergoes conformational changes comparable to those in the full-length protein. Recent efforts have focused on 1 obtaining crystals of the HBD suitable for x-ray diffraction analysis, 2 computer assisted modeling of the structure of the HBD, and 3 fluorescence studies to monitor ligand-induced conformational changes. Small crystals of the HBD have been obtained, although these are not yet suitable for diffraction analysis. Lacking crystallographic data, we performed structural modeling of the HBD. The model predicts that the core of the HBD remains essentially unaffected by ligand binding. We have used fluorescence spectroscopy to test this hypothesis, and these results also suggest that the HBD core is largely unaffected by ligand binding all three of the HBD tryptophan residues appear to be located in hydrophobic environments in the presence and absence of ligand. Trp383, located close to the estradiol binding site, was perturbed slightly by ligand binding.

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  • Biochemistry
  • Medicine and Medical Research

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