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Lookup NU author(s): Dr Oliver Coleman, Dr Tom McAllisterORCiD, Siddique Amin, Professor Akane Kawamura
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Plant homeodomain fingers (PHD-fingers) are a family of reader domains that can recruit epigenetic proteins to specific histone modification sites. Many PHD-fingers recognise methylated lysines on histone tails and play crucial roles in transcriptional regulation, with their dysregulation linked to various human diseases. Despite their biological importance, chemical inhibitors for targeting PHD-fingers are very limited. Here we report a potent and selective de novo cyclic peptide inhibitor (OC9) targeting the Nε-trimethyllysine-binding PHD‑fingers of the KDM7 histone demethylases, developed using mRNA display. OC9 disrupts PHD-finger interaction with histone H3K4me3, by engaging the Nε-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.
Author(s): Coleman OD, Macdonald J, Thomson B, Ward JA, Stubbs CJ, McAllister TE, Clark S, Amin S, Cao Y, Abboud MI, Zhang Y, Sanganee H, Huber KVM, Claridge TDW, Kawamura A
Publication type: Article
Publication status: Published
Journal: Chemical Science
Year: 2023
Volume: 14
Issue: 26
Pages: 7136-7146
Online publication date: 17/04/2023
Acceptance date: 15/04/2023
Date deposited: 13/06/2023
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/D2SC05944D
DOI: 10.1039/D2SC05944D
Data Access Statement: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD027151.
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