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Correlation between in Vitro Peptide Binding Profiles and Cellular Activities for Estrogen Receptor-Modulating Compounds

Department of Gene Expression and Protein Biochemistry (M.A.I., C.A.S., S.H.K., S.-J.D., T.G.C., J.S., J.G.G., K.H.P) and Department of Cheminformatics (D.L.S., D.E.V.), Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Kenneth H. Pearce, GlaxoSmithKline, P.O. Box 13398, Five Moore Drive, Research Triangle Park, North Carolina 27709. E-mail: kenneth.h.pearce{at}gsk.com.

Numerous biochemical and structural studies have shown that the conformation of the estrogen receptor (ER) can be influenced by ligand binding. In turn, the conformational state of ER affects the ability of the receptor to interact with a wide variety of protein accessory factors. To globally investigate ligand-based cofactor recruitment activities of ER, we have applied a flow cytometric multiplexed binding assay to determine the simultaneous binding of ER to over 50 different peptides derived from both known cofactor proteins and random peptide phage display. Using over 400 ER-binding compounds, we have observed that the multiplexed in vitro peptide-binding profiles are distinct for a number of compounds and that these profiles can predict the effect that ER ligands have on various cellular activities. These cell-based activities include transcriptional regulation at an estrogen response element, MCF-7 cell proliferation, and Ishikawa endometrial cell stimulation. The majority of the compound-induced diversity in the peptide profiling assay is provided by the unique phage display peptides. Importantly, some of these peptides show a sequence relationship with the corepressor motif, suggesting that peptides identified via phage display might represent natural binding partners of ER. These in vitro:cellular correlations may in part explain tissue-specific activities of ER-modulating compounds.

NURSA Molecule Pages Link:

Nuclear Receptors:   DAX1  |  SHP  |  ERα

Coregulators:   RIP140  |  TRAP220  |  PGC-1  |  SRC-1  |  GRIP1  |  AIB1  |  ASC-2  |  NCOR  |  SMRT

Ligands:   17β-Estradiol  |  Diethylstilbestrol  |  4-Hydroxytamoxifen  |  Raloxifene

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