Mimicking the Nucleosomal Context in Peptide-Based Binders of a H3K36me Reader Increases Binding Affinity While...

Area of Science:

• Epigenetics and molecular biology
• Drug discovery and medicinal chemistry

Background:

• Targeting histone modification machinery is a key strategy for disease treatment.
• Developing inhibitors for methyllysine readers, particularly H3K36me3 readers, is challenging due to shallow binding pockets and DNA interaction requirements.

Purpose of the Study:

• To design and characterize peptide-based binders for the H3K36me3 reader protein PSIP1.
• To investigate the role of nucleosomal context, specifically DNA interactions, in H3K36me3 recognition.

Main Methods:

• Peptide design incorporating negatively charged Glu-rich regions to mimic nucleosomal context.
• Nuclear Magnetic Resonance (NMR) spectroscopy for detailed binding analysis.

Main Results:

• Designed peptides incorporating negative charges increased binding affinity to PSIP1 up to 50-fold.
• Enhanced binding was attributed to interactions beyond the trimethyllysine binding pocket, involving DNA mimicry.
• Increased negative charge reduced direct binding to the trimethyllysine pocket.

Conclusions:

• Peptide design strategies mimicking the nucleosomal context can overcome challenges in targeting H3K36me3 readers.
• Binding affinity measurements alone are insufficient for compound selection; binding mode must be considered, especially for H3K36me3 readers.
• This approach offers a novel avenue for developing epigenetic drugs targeting H3K36me3 pathways.