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 N^ε-trimethyllysine-binding PHD-fingers of the KDM7 histone demethylases, developed using mRNA display. OC9 disrupts PHD-finger interaction with histone H3K4me3 by engaging the N^ε-methyllysine-binding aromatic cage through a valine, revealing

SUBMITTER: Coleman OD 

PROVIDER: S-EPMC10321576 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature