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A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode.

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.

SUBMITTER: Pande V

PROVIDER: S-EPMC7667828 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode.

Pande Vineet V Sun Weimei W Beke Lijs L Berthelot Didier D Brehmer Dirk D Brown David D Corbera Jordi J Irving Steve S Meerpoel Lieven L Nys Thomas T Parade Marc M Robinson Colin C Sommen Cois C Viellevoye Marcel M Wu Tongfei T Thuring Jan Willem JW

ACS medicinal chemistry letters 20200928 11

Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using <i>S</i>-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 cof ...[more]

PMID: 33214833

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