Protein arginine methyltransferase 5 (PRMT5) in complex with 5'-methylthioadenosine (MTA) (PRMT5-MTA)

Protein arginine methyltransferase 5 (PRMT5) is a type II methyltransferase that catalyzes the symmetric dimethylation of arginine residues on both histone and non-histone proteins, playing a critical role in RNA splicing, protein translation, and signal transduction (UniProt P55895). In approximately 15% of all human cancers, the methylthioadenosine phosphorylase (MTAP) gene is homozygously deleted, leading to the accumulation of the metabolite 5'-methylthioadenosine (MTA) (Kryukov et al., Science, 2016). This accumulated MTA binds to the active site of PRMT5, forming a PRMT5-MTA complex that serves as a specific vulnerability in MTAP-deleted cells (Marjon et al., Cell Reports, 2016). Next-generation "MTA-cooperative" inhibitors, such as MRTX1719 and AMG 193, are designed to bind specifically to this complex, selectively inhibiting PRMT5 activity in tumor cells while sparing healthy tissues (Smith et al., Cancer Discovery, 2022). This targeted approach aims to minimize the hematological toxicities, such as anemia and thrombocytopenia, that limited the clinical utility of first-generation PRMT5 inhibitors (Muller et al., Expert Opinion on Therapeutic Targets, 2023).

Other names

PRMT5:MTA complexMTA-bound PRMT5PRMT5-MTA

MTA-cooperative inhibition of PRMT5 methyltransferase activity