The structure and function of YTHDF epitranscriptomic m6A readers

Distinctive structural differences in the m6A-RNA-binding proteins DF1–DF3 imply functional differences and lay the foundations for paralog-selective drug design.Differences between the DF paralogs in post-translational modifications, and likely also in their conformational states, allostery, and allosteric site cooperativity upon ligand binding, offer further possibilities for paralog-selective inhibition.The DF paralogs have emerged as dynamic scaffold-like proteins which, upon binding to their m6A-mRNA targets, context-dependently bind to other partners such as their effectors.The paralog-selective inhibitors identified so far can be expected to help to further unravel the unique functions of DF paralogs. In turn, increased understanding of the disease-driving functions of the DF paralogs will enable mechanism-based design of more targeted and potent therapeutic inhibitors.