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 6W 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.