Structural Basis of Inhibition of ERα-Coactivator Interaction by High-Affinity N-Terminus Isoaspartic Acid Tethered Helical Peptides.

Direct inhibition of the protein-protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6 could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein-protein interactions involved in a range of disorders.