Pliability in the m 6 A-Binding Region Extends Druggability of YTH Domains.

Autor: Cazzanelli G; Department of Cellular, Computational and Integrative Biology─CIBIO, University of Trento, via Sommarive 9, 38123 Povo, Trento, Italy., Dalle Vedove A; Department of Cellular, Computational and Integrative Biology─CIBIO, University of Trento, via Sommarive 9, 38123 Povo, Trento, Italy., Spagnolli G; Department of Cellular, Computational and Integrative Biology─CIBIO, University of Trento, via Sommarive 9, 38123 Povo, Trento, Italy., Terruzzi L; Sibylla Biotech S.p.A, Via Lillo del Duca 10, 20091 Bresso, Milan, Italy., Colasurdo E; Sibylla Biotech S.p.A, Via Lillo del Duca 10, 20091 Bresso, Milan, Italy., Boldrini A; Sibylla Biotech S.p.A, Via Lillo del Duca 10, 20091 Bresso, Milan, Italy., Patsilinakos A; Sibylla Biotech S.p.A, Via Lillo del Duca 10, 20091 Bresso, Milan, Italy., Sturlese M; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy., Grottesi A; CINECA, Via dei Tizii, 6, 00185 Roma, Italy., Biasini E; Department of Cellular, Computational and Integrative Biology─CIBIO, University of Trento, via Sommarive 9, 38123 Povo, Trento, Italy., Provenzani A; Department of Cellular, Computational and Integrative Biology─CIBIO, University of Trento, via Sommarive 9, 38123 Povo, Trento, Italy., Quattrone A; Department of Cellular, Computational and Integrative Biology─CIBIO, University of Trento, via Sommarive 9, 38123 Povo, Trento, Italy., Lolli G; Department of Cellular, Computational and Integrative Biology─CIBIO, University of Trento, via Sommarive 9, 38123 Povo, Trento, Italy.
Jazyk: angličtina
Zdroj: Journal of chemical information and modeling [J Chem Inf Model] 2024 Mar 11; Vol. 64 (5), pp. 1682-1690. Date of Electronic Publication: 2024 Feb 28.
DOI: 10.1021/acs.jcim.4c00051
Abstrakt: 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 m 6 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.
Databáze: MEDLINE
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