Perturbation of estrogen receptor alpha localization with synthetic nona-arginine LXXLL-peptide coactivator binding inhibitors.
The interaction of estrogen receptor alpha (ERalpha) with the consensus LXXLL motifs of transcriptional coactivators provides an entry for functional ERalpha inhibition. Here, synthetic cell-permeable LXXLL peptide probes are brought forward that allow evaluation of the interaction of specific recognition motifs with ERalpha 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 ERalpha. The probes compete with coactivators, bind ERalpha, and recruit it into the nucleoli. The physical inhibition of the ERalpha-coactivator interaction by the probes is shown to be correlated with the inhibition of ERalpha-mediated gene transcription. This chemical biology approach allows evaluating the ERalpha-coactivator interaction and inhibitor binding directly in cells.
Carraz
Maëlle
M
Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany; Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600MB Eindhoven, The Netherlands.
Zwart
Wilbert
W
Phan
Trang
T
Michalides
Rob
R
Brunsveld
Luc
L
D020816:Amino Acid Motifs; D002466:Cell Nucleolus / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D006801:Humans; D015336:Molecular Probe Techniques; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D014158:Transcription, Genetic / Q000187:drug effects
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009842:Oligopeptides; D010455:Peptides; C491427:nonaarginine