Structural diversity of the epigenetics pocketome

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Protein families regulating chromatin are crucial targets in oncology and other diseases.
• Selective inhibitor development hinges on unique structural features of target sites.
• Understanding the 'epigenetics pocketome' is vital for therapeutic advancements.

Purpose of the Study:

• To analyze structural similarities and differences in protein binding pockets involved in chromatin regulation.
• To identify challenges and opportunities for developing selective inhibitors against epigenetic targets.
• To provide a resource for exploring the structural diversity of epigenetic binding pockets.

Main Methods:

• Calculated pairwise structural distances for 575 protein structures.
• Analyzed 163 unique binding pockets in domains involved in histone, DNA, and RNA modifications.
• Utilized structural data from the Protein Data Bank.

Main Results:

• Binding site structural similarity does not consistently correlate with protein sequence similarity.
• Compounds targeting cofactors of protein arginine methyltransferases, lysine acetyltransferases, and sirtuins pose cross-target risks.
• Exploiting protein conformational plasticity is a viable strategy for achieving selective inhibition.

Conclusions:

• The structural landscape of epigenetic binding pockets presents both challenges and opportunities for drug discovery.
• A deeper understanding of structural diversity is essential for designing selective epigenetic inhibitors.
• An open-access interface is available to explore the epigenetics pocketome structure.