Molecular tools for structural studies of RNA methyltransferases – ARNtools

RNA methyltransferases (rMTases) catalyse methylation of RNA, most-often using S-adenosyl-L-methionine (SAM) as the cofactor. Frequently occurring methylations are the mono-methylation of adenine at position N1 (m1A) or N6 (m6A). This project aims at synthesising SAM-RNA conjugates as m1A and m6A rMTase transition-state analogues. We propose a strategy involving post-functionalisation of the RNA, allowing us to produce SAM-RNA conjugates coupled at position N1 or N6 of the adenine, with a variety of lengths and sequences for the RNA. Structural and functional studies of five m1A or m6A rMTases will be perform with different types of SAM-RNA conjugates because some of them present therapeutic perspective. This will provide insights into the RNA/rMTase interactions to ultimately fully decipher the catalytic mechanism of adenosine methylation. We will further use the structural data obtained here to assist in structure-based drug design of potent inhibitors of rMTases.