Selective inhibition of the kinase DYRK1A by targeting its folding process
書誌事項
- 公開日
- 2016-04-22
- 資源種別
- journal article
- 権利情報
-
- This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
- DOI
-
- 10.1038/ncomms11391
- 公開者
- Nature Publishing Group
説明
Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors.
収録刊行物
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- Nature Communications
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Nature Communications 7 11391-, 2016-04-22
Nature Publishing Group
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キーワード
- Protein Folding
- Embryo, Nonmammalian
- Science
- Molecular Sequence Data
- Protein Serine-Threonine Kinases
- Transfection
- Dyrk Kinases
- Article
- Xenopus laevis
- Okadaic Acid
- Animals
- Humans
- Amino Acid Sequence
- Phosphorylation
- Oxazoles
- Protein Kinase Inhibitors
- Q
- Gene Expression Regulation, Developmental
- Protein-Tyrosine Kinases
- Recombinant Proteins
- Thiazoles
- HEK293 Cells
- Cantharidin
- Biological Assay
- Marine Toxins
- Sequence Alignment
- Biomarkers
- Plasmids
詳細情報 詳細情報について
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- CRID
- 1050845760765735040
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- NII論文ID
- 120005770755
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- ISSN
- 20411723
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- HANDLE
- 2433/215367
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- PubMed
- 27102360
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- 本文言語コード
- en
-
- 資料種別
- journal article
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- データソース種別
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