We report a crystallographic analysis of small-molecule ligands of the human YTHDC1 domain that recognizes N6methylated adenine (m 6 A) 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 −NHCH 3 group of m 6 A. 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 m 6 A reader domains. The structural information is useful for the design of modulators of m 6 A recognition by YTHDC1.
We report 17 small-molecule ligands that compete with
N6
-methyladenosine (m
6
A) for binding to
the m
6
A-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.
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