Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2.
Yasuaki Tokodai1, Mark Matyas2,3, Azumi Ishigamori1
1Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Biorxiv : the Preprint Server for Biology
|July 11, 2025
Summary
Researchers designed a cyclic peptide to activate Polycomb repressive complex 2 (PRC2). This peptide enhances H3K27 trimethylation, showing potential for cancer therapy and research into epigenetic regulation.
Area of Science:
- Biochemistry
- Epigenetics
- Structural Biology
Background:
- Polycomb repressive complex 2 (PRC2) dysregulation drives cancer by silencing tumor suppressors and activating oncogenes.
- Targeting PRC2 is a promising strategy for cancer research and therapeutics.
Purpose of the Study:
- To design and optimize a cyclic peptide that robustly activates PRC2.
- To investigate the structural and functional consequences of PRC2 activation by the peptide.
Main Methods:
- Structure-activity relationship studies for peptide optimization.
- Cryo-electron microscopy (cryo-EM) to determine the PRC2-peptide complex structure.
- Biochemical assays to assess H3K27 methylation states.
Main Results:
- A Phenylalanine-type (Phe-type) cyclic peptide was developed, achieving eight-fold PRC2 activation.
- Cryo-EM and biochemical analyses revealed a shift in H3K27 methylation from me1/me2 to me3.
- The cyclic peptide demonstrated enhanced stability in mouse plasma and cellular uptake, inducing H3K27 trimethylation in vitro and in cells.
Conclusions:
- The designed cyclic peptide effectively activates PRC2 and modulates H3K27 methylation.
- This peptide serves as a valuable tool for studying PRC2 function and targeting aberrant H3K27 methylation in cancer.
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