Issue 26, 2023

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

Abstract

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
26 okt 2022
Accepted
15 apr 2023
First published
17 apr 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 7136-7146

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

O. D. Coleman, J. Macdonald, B. Thomson, J. A. Ward, C. J. Stubbs, T. E. McAllister, S. Clark, S. Amin, Y. Cao, M. I. Abboud, Y. Zhang, H. Sanganee, K. V. M. Huber, T. D. W. Claridge and A. Kawamura, Chem. Sci., 2023, 14, 7136 DOI: 10.1039/D2SC05944D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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