Open AccessDiscovery of Small Molecules that Activate RNA Methylation through Cooperative Binding to the METTL3-14-WTAP Complex Active Site
Author(s) -
Simona Selberg,
Daria Blokhina,
Maria Aatonen,
Pertti Koivisto,
Antti Siltanen,
Eero Mervaala,
Esko Kankuri,
Mati Karelson
Publication year - 2019
Publication title -
cell reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.264
H-Index - 154
eISSN - 2639-1856
pISSN - 2211-1247
DOI - 10.1016/j.celrep.2019.02.100
Subject(s) - methyltransferase , rna , small molecule , biology , methylation , n6 methyladenosine , in silico , rna methylation , microbiology and biotechnology , enzyme , binding site , biochemistry , function (biology) , chemistry , computational biology , dna , gene
Chemical modifications of RNA provide an additional, epitranscriptomic, level of control over cellular functions. N-6-methylated adenosines (m6As) are found in several types of RNA, and their amounts are regulated by methyltransferases and demethylases. One of the most important enzymes catalyzing generation of m6A on mRNA is the trimer N-6-methyltransferase METTL3-14-WTAP complex. Its activity has been linked to such critical biological processes as cell differentiation, proliferation, and death. We used in silico-based discovery to identify small-molecule ligands that bind to METTL3-14-WTAP and determined experimentally their binding affinity and kinetics, as well as their effect on enzymatic function. We show that these ligands serve as activators of the METTL3-14-WTAP complex.
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