Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function

Journal article

-methyllysine-binding aromatic cage through a valine, revealing a new non-lysine recognition motif for the PHD-fingers that does not require cation-π interaction. PHD-finger inhibition by OC9 impacted JmjC-domain mediated demethylase activity at H3K9me2, leading to inhibition of KDM7B (PHF8) but stimulation of KDM7A (KIAA1718), representing a new approach for selective allosteric modulation of demethylase activity. Chemoproteomic analysis showed selective engagement of OC9 with KDM7s in T cell lymphoblastic lymphoma SUP T1 cells. Our results highlight the utility of mRNA-display derived cyclic peptides for targeting challenging epigenetic reader proteins to probe their biology, and the broader potential of this approach for targeting protein-protein interactions.

Authors: Coleman, OD; Macdonald, J; Thomson, B; Ward, JA; Stubbs, CJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: Chemical Science
• Volume: 14
• Issue: 26
• Pages: 7136-7146
• Publication date: 2023-07-05
• DOI: 10.1039/d2sc05944d
• EISSN: 2041-6539
• ISSN: 2041-6520
• Language: English
• Keywords: PHD finger; Peptide; Chemistry; Cyclic peptide; Biochemistry; Lysine; Cell biology; Amino acid; Transcription factor; Epigenetics; Computational biology; Domain (mathematical analysis); Biology; Gene; Function (biology); Demethylase; Zinc finger