Related Experiment Video
Updated: Jan 25, 2026
Gene-targeted Random Mutagenesis to Select Heterochromatin-destabilizing Proteasome Mutants in Fission Yeast
Published on: May 15, 2018
Discovery of selective activators of PRC2 mutant EED-I363M
Junghyun L Suh1, Kimberly D Barnash1,2, Tigran M Abramyan1
1Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
Abstract:
Many common disease-causing mutations result in loss-of-function (LOF) of the proteins in which they occur. LOF mutations have proven recalcitrant to pharmacologic intervention, presenting a challenge for the development of targeted therapeutics. Polycomb repressive complex 2 (PRC2), which contains core subunits (EZH2, EED, and SUZ12), regulates gene activity by trimethylation of histone 3 lysine 27. The dysregulation of PRC2 catalytic activity by mutations has been implicated in cancer and other diseases. Among the mutations that cause PRC2 malfunction, an I363M LOF mutation of EED has been identified in myeloid disorders, where it prevents allosteric activation of EZH2 catalysis. We describe structure-based design and computational simulations of ligands created to ameliorate this LOF. Notably, these compounds selectively stimulate the catalytic activity of PRC2-EED-I363M over wildtype-PRC2. Overall, this work demonstrates the feasibility of developing targeted therapeutics for PRC2-EED-I363M that act as allosteric agonists, potentially correcting this LOF mutant phenotype.
Insights
Targeting loss-of-function mutations in Polycomb repressive complex 2 (PRC2) is challenging. Researchers designed novel compounds that selectively activate mutant PRC2, offering a potential therapeutic strategy for myeloid disorders.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Loss-of-function (LOF) mutations are common in diseases and difficult to treat.
- Polycomb repressive complex 2 (PRC2) regulates gene activity via histone methylation.
- PRC2 mutations, like EED I363M in myeloid disorders, disrupt its function.
Purpose of the Study:
- To develop targeted therapeutics for LOF mutations in PRC2.
- To design ligands that can restore the catalytic activity of mutant PRC2.
- To investigate structure-based approaches for correcting EED I363M LOF phenotypes.
Main Methods:
- Structure-based drug design.
- Computational simulations of ligand-protein interactions.
- Biochemical assays to assess PRC2 catalytic activity.
Main Results:
- Novel compounds were designed to target the EED I363M mutation.
- These compounds selectively stimulate the catalytic activity of mutant PRC2 (PRC2-EED-I363M).
- Activity of the designed compounds was significantly higher on mutant PRC2 compared to wildtype PRC2.
Conclusions:
- Targeted therapeutics can be developed for LOF mutations in PRC2.
- Allosteric agonists can potentially correct the EED I363M LOF mutant phenotype.
- This work demonstrates a feasible strategy for developing drugs against challenging LOF mutations.
Related Concept Videos
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...
01:26Drug Discovery: Overview
01:32What is Natural Selection?
00:57Antibiotic Selection
01:46Types of Selection
01:21Frequency-dependent Selection