دورية أكاديمية

Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.

التفاصيل البيبلوغرافية
العنوان: Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.
المؤلفون: Szewczyk MM; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Ishikawa Y; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan., Organ S; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Sakai N; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan., Li F; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Halabelian L; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Ackloo S; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Couzens AL; Network Biology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute, 600 University Ave, Room 992, Toronto, ON, M5G 1X5, Canada., Eram M; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Dilworth D; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Fukushi H; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan., Harding R; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Dela Seña CC; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Sugo T; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan., Hayashi K; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan., McLeod D; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada., Zepeda C; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada., Aman A; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada., Sánchez-Osuna M; Institute for Research in Immunology and Cancer (IRIC) University of Montreal, 2950 Chemin de Polytechnique, Montreal, QC, H3T 1J4, Canada., Bonneil E; Institute for Research in Immunology and Cancer (IRIC) University of Montreal, 2950 Chemin de Polytechnique, Montreal, QC, H3T 1J4, Canada., Takagi S; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan., Al-Awar R; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada., Tyers M; Institute for Research in Immunology and Cancer (IRIC) University of Montreal, 2950 Chemin de Polytechnique, Montreal, QC, H3T 1J4, Canada., Richard S; Terry Fox Molecular Oncology Group and Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research and Departments of Oncology and Medicine, McGill University, Montreal, QC, H3T 1E2, Canada., Takizawa M; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan., Gingras AC; Network Biology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute, 600 University Ave, Room 992, Toronto, ON, M5G 1X5, Canada., Arrowsmith CH; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.; Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada., Vedadi M; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada., Brown PJ; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada., Nara H; Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan. nara@pharm.or.jp., Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. d.barsyte@utoronto.ca.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada. d.barsyte@utoronto.ca.; Nature Research Center, Vilnius, Akademijos 2, Lithuania. d.barsyte@utoronto.ca.
المصدر: Nature communications [Nat Commun] 2020 May 14; Vol. 11 (1), pp. 2396. Date of Electronic Publication: 2020 May 14.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Stress, Physiological*, Arginine/*metabolism , HSP70 Heat-Shock Proteins/*metabolism , Protein-Arginine N-Methyltransferases/*metabolism, Animals ; Gene Knockdown Techniques ; HCT116 Cells ; Humans ; Methylation/drug effects ; Protein Processing, Post-Translational/drug effects ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors ; Protein-Arginine N-Methyltransferases/genetics ; Recombinant Proteins/genetics ; Recombinant Proteins/isolation & purification ; Recombinant Proteins/metabolism ; Sf9 Cells
مستخلص: Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.
التعليقات: Erratum in: Nat Commun. 2020 May 26;11(1):2683. (PMID: 32457299)
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معلومات مُعتمدة: S10 OD021527 United States OD NIH HHS; Canada CIHR; P30 GM124165 United States GM NIGMS NIH HHS; 106169/ZZ14/Z United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust
المشرفين على المادة: 0 (HSP70 Heat-Shock Proteins)
0 (Recombinant Proteins)
94ZLA3W45F (Arginine)
EC 2.1.1.319 (PRMT7 protein, human)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
تواريخ الأحداث: Date Created: 20200516 Date Completed: 20200831 Latest Revision: 20210514
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC7224190
DOI: 10.1038/s41467-020-16271-z
PMID: 32409666
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-020-16271-z