A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode
Vineet Pande, Weimei Sun, Lijs Beke, Didier Berthelot, Dirk Brehmer, David Brown, Jordi Corbera, Steve Irving, Lieven Meerpoel, Thomas Nys, Marc Paradé, Colin Robinson, Cois Sommen, Marcel Viellevoye, Tongfei Wu, Jan Willem Thuring
Abstract
Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using S-adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.