Fig. 1: Intracellular regulation of PRMT5 activity and development of chemical probes CBH-001 and CBH-002.
From: A BRET biosensor for measuring uncompetitive engagement of PRMT5 complexes in cells
A Wild-type cells have high levels of SAM and relatively low levels of MTA, due to concurrent SAM-biosynthesis (driven by MAT2A) and methionine salvage (driven by MTAP); here, PRMT5 is predominantly SAM-bound and active. B MTAP deletion leads to an accumulation of intracellular MTA, which eventually out-competes SAM for binding to PRMT5, reducing methyltransferase activity. MTA-cooperative inhibitors have high affinity for MTA-bound PRMT5, causing selective cancer cell killing. C Structures of the chemoproteomic affinity probe CBH-001 and BRET biosensor CBH-002 for NanoBRET target engagement assays.
