6RT6

The YTH domain of YTHDC1 protein in complex with GGm6AC oligonucleotide

Summary for 6RT6

• Entry DOI: 10.2210/pdb6rt6/pdb
• Descriptor: RNA (5'-R(*(6MZ)P*C)-3'), YTH domain-containing protein 1, SULFATE ION, ... (4 entities in total)
• Functional Keywords: protein-rna interaction, epitranscriptomics, rna binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 40619.64

Authors

Bedi, R.,Sledz, P.,Caflisch, A. (deposition date: 2019-05-22, release date: 2019-11-27, Last modification date: 2024-01-24)

Primary citation

Li, Y.,Bedi, R.K.,Wiedmer, L.,Huang, D.,Sledz, P.,Caflisch, A.
Flexible Binding of m6A Reader Protein YTHDC1 to Its Preferred RNA Motif.
J Chem Theory Comput, 15:7004-7014, 2019

PubMed Abstract: -Methyladenosine (mA) 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 mA-containing RNAs to their readers are still elusive due to the unclear roles of mA-flanking ribonucleotides. Here, we use a model system, YTHDC1 with its RNA motif 5'-GG(mA)CU-3', to investigate the binding mechanisms by atomistic simulations, X-ray crystallography, and isothermal titration calorimetry. The experimental data and simulation results show that mA 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 mA 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 mA reader proteins.

PubMed: 31670957
DOI: 10.1021/acs.jctc.9b00987

Experimental method

X-RAY DIFFRACTION (1.461 Å)