4jc3 | pdb_00004jc3
14-3-3 protein interaction with Estrogen Receptor Alpha provides a novel drug target interface
Structural highlights
Function1433S_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. Publication Abstract from PubMedEstrogen receptor alpha (ERalpha) is involved in numerous physiological and pathological processes, including breast cancer. Breast cancer therapy is therefore currently directed at inhibiting the transcriptional potency of ERalpha, either by blocking estrogen production through aromatase inhibitors or antiestrogens that compete for hormone binding. Due to resistance, new treatment modalities are needed and as ERalpha dimerization is essential for its activity, interference with receptor dimerization offers a new opportunity to exploit in drug design. Here we describe a unique mechanism of how ERalpha dimerization is negatively controlled by interaction with 14-3-3 proteins at the extreme C terminus of the receptor. Moreover, the small-molecule fusicoccin (FC) stabilizes this ERalpha/14-3-3 interaction. Cocrystallization of the trimeric ERalpha/14-3-3/FC complex provides the structural basis for this stabilization and shows the importance of phosphorylation of the penultimate Threonine (ERalpha-T(594)) for high-affinity interaction. We confirm that T(594) is a distinct ERalpha phosphorylation site in the breast cancer cell line MCF-7 using a phospho-T(594)-specific antibody and by mass spectrometry. In line with its ERalpha/14-3-3 interaction stabilizing effect, fusicoccin reduces the estradiol-stimulated ERalpha dimerization, inhibits ERalpha/chromatin interactions and downstream gene expression, resulting in decreased cell proliferation. Herewith, a unique functional phosphosite and an alternative regulation mechanism of ERalpha are provided, together with a small molecule that selectively targets this ERalpha/14-3-3 interface. Interaction of 14-3-3 proteins with the estrogen receptor alpha F domain provides a drug target interface.,De Vries-van Leeuwen IJ, da Costa Pereira D, Flach KD, Piersma SR, Haase C, Bier D, Yalcin Z, Michalides R, Feenstra KA, Jimenez CR, de Greef TF, Brunsveld L, Ottmann C, Zwart W, de Boer AH Proc Natl Acad Sci U S A. 2013 May 28;110(22):8894-9. doi:, 10.1073/pnas.1220809110. Epub 2013 May 15. PMID:23676274[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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