4JC3

14-3-3 protein interaction with Estrogen Receptor Alpha provides a novel drug target interface

Summary for 4JC3

• Entry DOI: 10.2210/pdb4jc3/pdb
• Related: 3MHR 3SMK 3TOM 3UX0 4JDD
• Descriptor: 14-3-3 protein sigma, Estrogen receptor Peptide, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: 14-3-3, adapter protein, protein-protein interaction, signaling protein-peptide complex, signaling protein/peptide
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P31947; Isoform 1: Nucleus . Isoform 3: Nucleus. Nucleus: P03372
• Total number of polymer chains: 2
• Total formula weight: 27773.94

Authors

Bier, D.,Ottmann, C. (deposition date: 2013-02-21, release date: 2013-05-15, Last modification date: 2024-11-06)

Primary citation

De Vries-van Leeuwen, I.J.,da Costa Pereira, D.,Flach, K.D.,Piersma, S.R.,Haase, C.,Bier, D.,Yalcin, Z.,Michalides, R.,Feenstra, K.A.,Jimenez, C.R.,de Greef, T.F.,Brunsveld, L.,Ottmann, C.,Zwart, W.,de Boer, A.H.
Interaction of 14-3-3 proteins with the estrogen receptor alpha F domain provides a drug target interface.
Proc. Natl. Acad. Sci. U.S.A., 110:8894-8899, 2013

PubMed Abstract: Estrogen receptor alpha (ERα) is involved in numerous physiological and pathological processes, including breast cancer. Breast cancer therapy is therefore currently directed at inhibiting the transcriptional potency of ERα, 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 ERα 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 ERα 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 ERα/14-3-3 interaction. Cocrystallization of the trimeric ERα/14-3-3/FC complex provides the structural basis for this stabilization and shows the importance of phosphorylation of the penultimate Threonine (ERα-T(594)) for high-affinity interaction. We confirm that T(594) is a distinct ERα 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 ERα/14-3-3 interaction stabilizing effect, fusicoccin reduces the estradiol-stimulated ERα dimerization, inhibits ERα/chromatin interactions and downstream gene expression, resulting in decreased cell proliferation. Herewith, a unique functional phosphosite and an alternative regulation mechanism of ERα are provided, together with a small molecule that selectively targets this ERα/14-3-3 interface.

PubMed: 23676274
DOI: 10.1073/pnas.1220809110

Experimental method

X-RAY DIFFRACTION (2.05 Å)