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

0 views • Sep 30, 2021
0
Save
Cite
Share

Author(s)

Author Name

Magda Szewczyk

Published 2 Projects

Biochemistry

Yoshinori Ishikawa

Published 1 Project

Biochemistry

Shawna Organ

Published 1 Project

Biochemistry

Nozomu Sakai

Published 1 Project

Biochemistry

Uploader

Fengling Li

Levon Halabelian

Published 2 Projects

Biochemistry

Suzanne Ackloo

Published 3 Projects

Biochemistry Cell Biology

Mohammad Eram

Published 1 Project

Biochemistry

David Dilworth

Hideto Fukushi

Published 1 Project

Biochemistry

Rachel J Harding

Published 1 Project

Biochemistry

Carlo C. dela Seña

Published 2 Projects

Biochemistry

Tsukasa Sugo

Published 1 Project

Biochemistry

Kozo Hayashi

Published 1 Project

Biochemistry

David Macleod

Published 1 Project

Biochemistry

Carlos Zepeda

Published 1 Project

Biochemistry

Shinji Takagi

Published 1 Project

Biochemistry

Rima Al-Awar

Stephane Richard

Published 1 Project

Biochemistry

Masayuki Takizawa

Published 1 Project

Biochemistry

Cheryl H Arrowsmith

Masoud Vedadi

Peter J Brown

Dalia Barsyte

Add New Author

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 resulted in drastically reduced levels of arginine monomethylation of HSP70 family members and other stress-associated proteins. Structural and biochemical analysis revealed that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibited methylation of both constitutive and inducible forms of HSP70, and led 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.

Biochemistry
Biochemistry 9 Projects