1. Pliability in the m 6 A-Binding Region Extends Druggability of YTH Domains.
- Author
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Cazzanelli G, Dalle Vedove A, Spagnolli G, Terruzzi L, Colasurdo E, Boldrini A, Patsilinakos A, Sturlese M, Grottesi A, Biasini E, Provenzani A, Quattrone A, and Lolli G
- Subjects
- Pliability, RNA, Messenger chemistry, RNA, Messenger metabolism, Molecular Conformation, RNA-Binding Proteins chemistry, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism
- Abstract
Epitranscriptomic mRNA modifications affect gene expression, with their altered balance detected in various cancers. YTHDF proteins contain the YTH reader domain recognizing the m
6 A mark on mRNA and represent valuable drug targets. Crystallographic structures have been determined for all three family members; however, discrepancies are present in the organization of the m6 A-binding pocket. Here, we present new crystallographic structures of the YTH domain of YTHDF1, accompanied by computational studies, showing that this domain can exist in different stable conformations separated by a significant energetic barrier. During the transition, additional conformations are explored, with peculiar druggable pockets appearing and offering new opportunities for the design of YTH-interfering small molecules.- Published
- 2024
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