Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.

Publication Type:

Journal Article


Nat Commun, Volume 11, Issue 1, p.2396 (2020)


Animals, Arginine, Gene Knockdown Techniques, HCT116 Cells, HSP70 Heat-Shock Proteins, Humans, Methylation, Protein Processing, Post-Translational, Protein-Arginine N-Methyltransferases, Recombinant Proteins, Sf9 Cells, Stress, Physiological


<p>Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.</p>