Perturbation of estrogen receptor α localization with synthetic nona-arginine LXXLL-peptide coactivator binding inhibitors

The interaction of estrogen receptor a (ERa) with the consensus LXXLL motifs of transcriptional coactivators provides an entry for functional ERa inhibition. Here, synthetic cell-permeable LXXLL peptide probes are brought forward that allow evaluation of the interaction of specific recognition motifs with ERa in the context of the cell. The probes feature a nona-arginine tag that facilitates cellular entry and induces probe localization in nucleoli. The nucleoli localization provides an explicit tool for evaluating the LXXLL motif interaction with ERa. The probes compete with coactivators, bind ERa, and recruit it into the nucleoli. The physical inhibition of the ERa-coactivator interaction by the probes is shown to be correlated with the inhibition of ERa-mediated gene transcription. This chemical biology approach allows evaluating the ERa-coactivator interaction and inhibitor binding directly in cells.