Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 11, Pages 2227-2231Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00355
Keywords
PRMT5; Spirodiamines; Methyltransferase; Chemical Probe; Protein flexibility
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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.
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