Fragment Ligands of the m<sup>6</sup>A-RNA Reader YTHDF2
Francesco Nai, Raed Nachawati, František Zálešák, Xiang Wang, Yaozong Li, Amedeo Caflisch
Abstract
We report 17 small-molecule ligands that compete with N6-methyladenosine (m6A) for binding to the m6A-reader domain of YTHDF2 (YT521-B homology domain family 2). We determined their binding mode at high resolution by X-ray crystallography and quantified their affinity by a fluorescence-based binding assay. 6-Cyclopropyluracil and a pyrazolopyrimidine derivative have favorable ligand efficiencies of 0.47 and 0.38 kcal mol–1 per non-hydrogen atom, respectively. They represent useful starting points for hit optimization.
Topics & Concepts
RNAChemistryLigand (biochemistry)FluorescenceDerivative (finance)MoleculeStereochemistryCrystallographyComputational biologyBiologyBiochemistryGenePhysicsReceptorFinancial economicsQuantum mechanicsOrganic chemistryEconomicsRNA modifications and cancerRNA Research and SplicingRNA and protein synthesis mechanisms