Protein arginine N-methyltransferase 5–methylthioadenosine complex (PRMT5–MTA complex)

Protein arginine N-methyltransferase 5 (PRMT5) is a type II methyltransferase enzyme that catalyzes the symmetric dimethylation of arginine residues in histone and non-histone proteins, thereby playing a central role in gene regulation and chromatin structure[1][2][4][6][8]. The PRMT5–MTA complex refers to the state of PRMT5 bound to methylthioadenosine (MTA), a metabolite that accumulates in MTAP-deficient cancer cells and acts as a natural cofactor as well as a selective vulnerability[3][5][7][9]. This complex forms the structural and pharmacological basis for the development of inhibitors that exploit synthetic lethality in MTAP-deleted cancers. These inhibitors exhibit increased potency and selectivity when PRMT5 is complexed with MTA, as this allosterically alters the enzyme’s conformation and binding site accessibility, facilitating preferential inhibition over the SAM-bound state[3][7][9]. PRMT5–MTA targeting drugs are in clinical development, primarily for cancer indications, and are being explored as potential “precision medicine” therapies for tumors with MTAP loss.

Other names

PRMT5–MTA complexPRMT5/MTA complexPRMT5 in complex with methylthioadenosinePRMT5 (when the context implies MTA-bound form)

Competitive inhibition of the substrate (arginine) binding site Selective inhibition by exploiting the unique conformational state of the PRMT5–MTA complex (synthetic lethality in MTAP−/− cancer) Allosteric modulation via protein–protein interaction disruption (MEP50, SAPs)