Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5)
- Rachel L. Palte*Rachel L. Palte*Email: [email protected]Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Rachel L. Palte
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- Sebastian E. Schneider*Sebastian E. Schneider*Email: [email protected]Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Sebastian E. Schneider
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- Michael D. AltmanMichael D. AltmanComputational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Michael D. Altman
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- Robert P. HayesRobert P. HayesComputational and Structural Chemistry, West Point, Pennsylvania 19486, United StatesMore by Robert P. Hayes
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- Shuhei KawamuraShuhei KawamuraDiscovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Shuhei Kawamura
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- Brian M. LaceyBrian M. LaceyQuantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Brian M. Lacey
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- My Sam MansuetoMy Sam MansuetoQuantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by My Sam Mansueto
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- Michael ReutershanMichael ReutershanDiscovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Michael Reutershan
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- Phieng SiliphaivanhPhieng SiliphaivanhDiscovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Phieng Siliphaivanh
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- Christopher SondeyChristopher SondeyQuantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Christopher Sondey
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- Haiyan XuHaiyan XuQuantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Haiyan Xu
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- Zangwei XuZangwei XuQuantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Zangwei Xu
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- Yingchun YeYingchun YeDiscovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Yingchun Ye
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- Michelle R. MachacekMichelle R. MachacekDiscovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United StatesMore by Michelle R. Machacek
Abstract

Protein arginine methyltransferase 5 (PRMT5) belongs to a family of enzymes that regulate the posttranslational modification of histones and other proteins via methylation of arginine. Methylation of histones is linked to an increase in transcription and regulates a manifold of functions such as signal transduction and transcriptional regulation. PRMT5 has been shown to be upregulated in the tumor environment of several cancer types, and the inhibition of PRMT5 activity was identified as a potential way to reduce tumor growth. Previously, four different modes of PRMT5 inhibition were known—competing (covalently or non-covalently) with the essential cofactor S-adenosyl methionine (SAM), blocking the substrate binding pocket, or blocking both simultaneously. Herein we describe an unprecedented conformation of PRMT5 in which the formation of an allosteric binding pocket abrogates the enzyme’s canonical binding site and present the discovery of potent small molecule allosteric PRMT5 inhibitors.
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