Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function
Oliver D. Coleman, Jessica L. MacDonald, Ben Thomson, Jennifer Ward, Christopher J. Stubbs, Tom E. McAllister, Shane Clark, Siddique Amin, Yimang Cao, Martine I. Abboud, Yijia Zhang, Hitesh J. Sanganee, K. Huber, Timothy D. W. Claridge, Akane Kawamura
Abstract
-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.