A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode,ACS Medicinal Chemistry Letters

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A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-09-28 , DOI: 10.1021/acsmedchemlett.0c00355
Vineet Pande ₁ , Weimei Sun ₂ , Lijs Beke ₁ , Didier Berthelot ₃ , Dirk Brehmer ₁ , David Brown ₄ , Jordi Corbera ₅ , Steve Irving ₄ , Lieven Meerpoel ₁ , Thomas Nys ₁ , Marc Parade ₁ , Colin Robinson ₄ , Cois Sommen ₁ , Marcel Viellevoye ₁ , Tongfei Wu ₁ , Jan Willem Thuring ₁

Affiliation

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.

中文翻译：

具有新型结合模式的甲基转移酶 PRMT5 的化学探针

蛋白质精氨酸甲基转移酶 5 (PRMT5) 是一种酶，它可以使用S-腺苷甲硫氨酸 (SAM) 作为甲基供体辅助因子，对称地二甲基化组蛋白和非组蛋白中的精氨酸残基。我们设计了一个 SAM 类似物库，并发现了作为 PRMT5 酶功能抑制剂的强效、细胞活性和选择性螺二胺。晶体学研究证实了一种非常有趣的结合模式，涉及蛋白质灵活性，其中辅因子口袋和部分底物结合位点都被这些抑制剂占据。

更新日期：2020-11-12

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