Plant homeodomain targeting cyclic peptides allosterically modulate KDM7 histone demethylase activity

ABSTRACT: Here we report the discovery of a set of potent de-novo cyclic peptides (CPs) targeting different binding sites on KDM7B. One CP (OC9) bound directly to the KDM7 PHD-finger, as supported by bio-layer interferometry (BLI), isothermal calorimetry (ITC), hydrogen-deuterium exchange mass spectrometry (HDxMS) and NMR studies, and was highly selective for KDM7s over other PHD-fingers. OC9 disrupted PHD-finger binding to H3K4me3, and allosterically modulated KDM7 demethylase activity at H3K9me2 site on peptides and histone extracts demonstrating PHD-finger targeting is as JmjC-domain targeted inhibitors, but more selective for specific KDM7 subfamily member and certain combinatorial histone PTM signatures. Proteomic analysis confirmed OC9 to selectively target KDM7 in nuclear lysates demonstrating its high affinity and selectivity against other H3K4me3 reader domains and KDMs.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell

DISEASE(S): Lymphoma

SUBMITTER: Jennifer Ward  

LAB HEAD: Kilian Huber

PROVIDER: PXD027151 | Pride | 2023-07-20

REPOSITORIES: pride