Selectively disrupting m6A-dependent protein-RNA interactions with fragments

TitleSelectively disrupting m6A-dependent protein-RNA interactions with fragments
Publication TypeJournal Article
Year of Publication2020
AuthorsBedi R.K, Huang D., Wiedmer L., Li Y., Dolbois A., Wojdyla J.A, Sharpe M.E, Caflisch A., Śledź P.
JournalACS Chemical Biology
Volume15
Issue3
Pagination618-625
Date Published2020 Mar 20
Type of ArticleResearch Article
ISSN1554-8937
KeywordsFragment docking, m6A reader, RNA-Binding Proteins, SEED, X-ray crystallography
Abstract

We report a crystallographic analysis of small-molecule ligands of the human YTHDC1 domain that recognizes N6-methylated adenine (m6A) in RNA. The 30 binders are fragments (molecular weight < 300 g mol-1) that represent 10 different chemotypes identified by virtual screening. Despite the structural disorder of the binding site loop (residues 429-439), most of the 30 fragments emulate the two main interactions of the -NHCH3 group of m6A. These interactions are the hydrogen bond to the backbone carbonyl of Ser378 and the van der Waals contacts with the tryptophan cage. Different chemical groups are involved in the conserved binding motifs. Some of the fragments show favorable ligand efficiency for YTHDC1 and selectivity against other m6A reader domains. The structural information is useful for the design of modulators of m6A recognition by YTHDC1.

DOI10.1021/acschembio.9b00894
pubindex

0252

Alternate JournalACS Chem. Biol.
PubMed ID32101404
Highlight Role: 
Drug Design