The Crystal Structures of TrkA and TrkB Suggest Key Regions for Achieving Selective Inhibition |
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| Authors: | T. Bertrand M. Kothe J. Liu A. Dupuy A. Rak P.F. Berne S. Davis T. Gladysheva C. Valtre J.Y. Crenne M. Mathieu |
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| Affiliation: | 1. Department of Structure, Design, and Informatics, Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine, 94403 Cedex, France;2. Department of Biological Sciences, Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine, 94403 Cedex, France;3. In Vitro Biology, Genzyme Drug and Biomaterials, 153 Second Avenue, Waltham, MA 02451, USA;1. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States;2. Department of Chemistry Modeling and Informatics, Merck Research Laboratories, West Point, PA 19486, United States;3. Department of Neuroscience Research, Merck Research Laboratories, West Point, PA 19486, United States;4. Department of Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States;5. Department of In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States;6. Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States;3. Departments of Pathology and Laboratory Medicine and Emory University School of Medicine, Atlanta, Georgia 30322;5. Radiology and Imaging Sciences, Psychiatry, and Hematology and Oncology, Center for Systems Imaging, Wesley Woods Health Centers, Emory University School of Medicine, Atlanta, Georgia 30322 and;4. Departments of Chemistry and Biology, Center for Diagnostics and Therapeutics (CDT), Georgia State University, Atlanta, Georgia 30303;1. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical sciences, Hashemite University, Zarqa, Jordan;2. Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical sciences, Hashemite University, Zarqa, Jordan;3. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Zarqa University, Zarqa, Jordan;4. Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman, Jordan;1. School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia;2. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia;3. Clem Jones Centre for Ageing and Disease Research, The University of Queensland, Brisbane, Queensland, Australia;1. Unit of Molecular Basis of Neurodegeneration, Institute of Biomedicine CSIC, València, Spain;2. Department of Structural Biology, Laboratory of NMR-Spectroscopy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russian Federation;3. Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland, USA;4. Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Moscow, Russian Federation |
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| Abstract: | The Trk family of neurotrophin receptors, which includes the three highly homologous proteins TrkA, TrkB and TrkC, is strongly associated with central and peripheral nervous system processes. Trk proteins are also of interest in oncology, since Trk activation has been observed in several cancer types. While Trk kinases are attractive oncology targets, selectivity might be more of an issue than for other kinases due to potential CNS side effects if several Trk kinases are simultaneously targeted. In order to address this issue, we present here the first structures of human TrkA and TrkB kinase domains and three complexes between TrkB and Trk inhibitors. These structures reveal different conformations of the kinase domain and suggest new regions of selectivity among the Trk family. |
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