Selectively Disrupting m⁶A-Dependent Protein-RNA Interactions with Fragments

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• N6-methylated adenine (m⁶A) is a crucial RNA modification.
• YTHDC1 is a key protein domain that recognizes m⁶A modifications in RNA.
• Understanding YTHDC1-m⁶A interactions is vital for RNA biology and disease research.

Purpose of the Study:

• To perform a crystallographic analysis of small-molecule ligands binding to the human YTHDC1 domain.
• To identify and characterize fragments that mimic the binding interactions of m⁶A.
• To provide structural insights for designing modulators of YTHDC1 activity.

Main Methods:

• Crystallographic analysis of YTHDC1-ligand complexes.
• Virtual screening to identify potential small-molecule binders.
• Structure-based analysis of ligand-protein interactions.

Main Results:

• 30 small-molecule fragments (< 300 g mol^-1) representing 10 chemotypes were identified as YTHDC1 binders.
• Most fragments successfully emulate key interactions of the m⁶A N6-methyl group, including hydrogen bonding to Ser378 and van der Waals contacts with the tryptophan cage.
• Some identified fragments exhibit favorable ligand efficiency and selectivity for YTHDC1 over other m⁶A reader domains.

Conclusions:

• The identified fragments provide valuable structural information for understanding YTHDC1-m⁶A recognition.
• These findings can guide the rational design of novel therapeutic agents targeting YTHDC1-mediated pathways.
• The study highlights the potential of fragment-based drug design for modulating RNA epigenetic marks.