SNAP output for PDB entry 6rt6 [SNAP web server]

PDB-id

6rt6; SNAP-derived features in text and JSON formats; DNAproDB

Class

RNA binding protein

Method

X-ray (1.461 Å)

Summary

The yth domain of ythdc1 protein in complex with ggm6ac oligonucleotide

Reference

Li Y, Bedi RK, Wiedmer L, Huang D, Sledz P, Caflisch A (2019): "Flexible Binding of m6A Reader Protein YTHDC1 to Its Preferred RNA Motif." J Chem Theory Comput, 15, 7004-7014. doi: 10.1021/acs.jctc.9b00987.

Abstract

N₆-Methyladenosine (m₆A) is the most prevalent chemical modification in human mRNAs. Its recognition by reader proteins enables many cellular functions, including splicing and translation of mRNAs. However, the binding mechanisms of m₆A-containing RNAs to their readers are still elusive due to the unclear roles of m₆A-flanking ribonucleotides. Here, we use a model system, YTHDC1 with its RNA motif 5'-G_-2G_-1(m₆A)C₊₁U₊₂-3', to investigate the binding mechanisms by atomistic simulations, X-ray crystallography, and isothermal titration calorimetry. The experimental data and simulation results show that m₆A is captured by an aromatic cage of YTHDC1 and the 3' terminus nucleotides are stabilized by cation-π-π interactions, while the 5' terminus remains flexible. Notably, simulations of unbound RNA motifs reveal that the methyl group of m₆A and the 5' terminus shift the conformational preferences of the oligoribonucleotide to the bound-like conformation, thereby facilitating the association process. The binding mechanisms may help in the discovery of chemical probes against m₆A reader proteins.