Discovery and Optimization of Inhibitors of the Parkinson’s Disease Associated Protein DJ-1
- Shinya TashiroShinya TashiroDepartment of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, JapanInstitute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanMore by Shinya Tashiro
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- Jose M. M. Caaveiro*Jose M. M. Caaveiro*E-mail: [email protected]Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, JapanInstitute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanLaboratory of Global Healthcare, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanMore by Jose M. M. Caaveiro
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- Makoto NakakidoMakoto NakakidoDepartment of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, JapanInstitute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanMore by Makoto Nakakido
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- Aki TanabeAki TanabeDepartment of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, JapanMore by Aki Tanabe
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- Satoru NagatoishiSatoru NagatoishiDepartment of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, JapanInstitute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanMore by Satoru Nagatoishi
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- Yasushi TamuraYasushi TamuraDepartment of Material and Biological Chemistry, Faculty of Science, Yamagata University, Yamagata 990-8560, JapanMore by Yasushi Tamura
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- Noriyuki MatsudaNoriyuki MatsudaUbiquitin Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo 156-8506, JapanMore by Noriyuki Matsuda
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- Dali LiuDali LiuDepartment of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United StatesMore by Dali Liu
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- Quyen Q. HoangQuyen Q. HoangStark Neurosciences Research Institute and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United StatesMore by Quyen Q. Hoang
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- Kouhei Tsumoto*Kouhei Tsumoto*E-mail: [email protected]Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, JapanInstitute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanDepartment of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo 108-8639, JapanMore by Kouhei Tsumoto
Abstract
DJ-1 is a Parkinson’s disease associated protein endowed with enzymatic, redox sensing, regulatory, chaperoning, and neuroprotective activities. Although DJ-1 has been vigorously studied for the past decade and a half, its exact role in the progression of the disease remains uncertain. In addition, little is known about the spatiotemporal regulation of DJ-1, or the biochemical basis explaining its numerous biological functions. Progress has been hampered by the lack of inhibitors with precisely known mechanisms of action. Herein, we have employed biophysical methodologies and X-ray crystallography to identify and to optimize a family of compounds inactivating the critical Cys106 residue of human DJ-1. We demonstrate these compounds are potent inhibitors of various activities of DJ-1 in vitro and in cell-based assays. This study reports a new family of DJ-1 inhibitors with a defined mechanism of action, and contributes toward the understanding of the biological function of DJ-1.
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