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Updated: Jul 18, 2025
Sequence-specific Labeling of Nucleic Acids and Proteins with Methyltransferases and Cofactor Analogues
Published on: November 22, 2014
Structure-Based Design of Inhibitors of the m6A-RNA Writer Enzyme METTL3
Rajiv Kumar Bedi1, Danzhi Huang1, Yaozong Li1
1Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland.
Abstract:
Methyltransferase-like 3 (METTL3) and METTL14 form a heterodimeric complex that catalyzes the most abundant internal mRNA modification, N6-methyladenosine (m6A). METTL3 is the catalytic subunit that binds the co-substrate S-adenosyl methionine (SAM), while METTL14 is involved in mRNA binding. The m6A modification provides post-transcriptional level control over gene expression as it affects almost all stages of the mRNA life cycle, including splicing, nuclear export, translation, and decay. There is increasing evidence for an oncogenic role of METTL3 in acute myeloid leukemia. Here, we use structural and dynamic details of the catalytic subunit METTL3 for developing small-molecule inhibitors that compete with SAM. Starting from a hit identified by high-throughput docking, protein crystallography and molecular dynamics simulations were employed to guide the optimization of inhibitory activity. The potency was successfully improved by 8000-fold as measured by a homogeneous time-resolved fluorescence assay. The optimized compound is selective against the off-targets RNA methyltransferases METTL1 and METTL16.
Insights
Researchers developed small-molecule inhibitors targeting Methyltransferase-like 3 (METTL3), a key enzyme in mRNA modification linked to cancer. These inhibitors show significant potency and selectivity, offering a potential therapeutic strategy for diseases like acute myeloid leukemia.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Methyltransferase-like 3 (METTL3) and METTL14 form a complex catalyzing N-methyladenosine (m6A) mRNA modification.
- m6A modification regulates gene expression post-transcriptionally, impacting mRNA processing and function.
- METTL3 exhibits an oncogenic role, particularly in acute myeloid leukemia.
Purpose of the Study:
- To develop small-molecule inhibitors targeting the catalytic subunit METTL3.
- To design inhibitors that compete with the co-substrate S-adenosyl methionine (SAM).
Main Methods:
- Utilized structural and dynamic details of METTL3.
- Employed high-throughput docking to identify initial hits.
- Applied protein crystallography and molecular dynamics simulations for optimization.
- Assessed inhibitory activity using homogeneous time-resolved fluorescence assays.
Main Results:
- Achieved an 8000-fold improvement in inhibitory potency.
- Developed a compound selective against off-target RNA methyltransferases METTL1 and METTL16.
Conclusions:
- Successfully designed potent and selective small-molecule inhibitors of METTL3.
- These inhibitors represent a promising therapeutic avenue for METTL3-driven cancers, such as acute myeloid leukemia.
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