N6-methyladenosine (m6A) is the most prevalent and reversible co-transcriptional modification of mammalian RNA. This modification regulates the fate of m6A-containing RNA via translation, splicing and degradation. In human, the m6A modification is catalyzed by a heterodimer methyltransferase complex, which includes methyltransferase-like 3 (METTL3) and 14 (METTL14) so called writers. Demethylation of m6A is on the other hand mediated by two demethylases also called erasers: AlkB homologue 5 (ALKBH5) and fat mass obesity-associated protein (FTO). Upregulation of METTL3-METTL14 complex has been recently linked to aberrant gene expression and protein synthesis, leading to developmental defects and cancer progression.
METTL3 primarily functions as catalytically active subunit, containing co-factor S-adenosylmethionine (SAM) binding pocket while METTL14 serves as an RNA-binding platform. Here we present crystal structure of this complex with a high-resolution (1.8 Å) view of the catalytic site of METTL3 occupied by a co-factor competitive inhibitor PD-2082. This inhibitor is structurally based on previously reported STM2457 currently used for the research of acute myeloid leukaemia. This preliminary crystal structure provides a valuable structural insights for further rational design of the METTL3 inhibitors as potential drugs.