Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library
| العنوان: | Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library |
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| المؤلفون: | Jesús Jiménez-Barbero, María José Sánchez-Barrena, F. Javier Cañada, Elena Gómez-Rubio, Almudena Sáiz, Patricia Blanco-Gabella, Elena Sáez, Sara Baldominos, Naiara Pascual, Alicia Mansilla, Javier Sastre, Ángeles Canales, Dolores Molero, Sonsoles Martín-Santamaría, Loreto Martínez-González, Ana Martínez, Ruth Pérez-Fernández, Mª Encarnación Fernández-Valle, Andrea Canal-Martín |
| المساهمون: | Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundación BBVA, La Caixa, Sastre, Javier, Canales, Ángeles, Martín-Santamaría, Sonsoles, Sáiz, Almudena, Mansilla, A., Cañada, F. Javier, Jiménez-Barbero, Jesús, Martínez, Ana, Pérez-Fernández, Ruth, Sastre, Javier [0000-0002-1217-1558], Canales, Ángeles [0000-0003-0542-3080], Martín-Santamaría, Sonsoles [0000-0002-7679-0155], Sáiz, Almudena [0000-0001-9396-5386], Mansilla, A. [0000-0002-2192-5112], Cañada, F. Javier [000-0003-4462-1469], Jiménez-Barbero, Jesús [0000-0001-5421-8513], Martínez, Ana [0000-0002-2707-8110], Pérez-Fernández, Ruth [0000-0003-0148-6455] |
| المصدر: | Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) Nature Communications Digital.CSIC. Repositorio Institucional del CSIC instname |
| بيانات النشر: | Nature Publishing Group, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Chemical process, Male, Protein Conformation, Science, Neuronal Calcium-Sensor Proteins, General Physics and Astronomy, 02 engineering and technology, Computational biology, Reaction intermediate, General Biochemistry, Genetics and Molecular Biology, Catalysis, Permeability, Article, 03 medical and health sciences, Mice, Molecular recognition, Protein structure, Dynamic combinatorial chemistry, Animals, Combinatorial Chemistry Techniques, lcsh:Science, Cells, Cultured, Gene Library, Neurons, Multidisciplinary, Drug discovery, Chemistry, Ligand, fungi, Proteins, Membranes, Artificial, General Chemistry, 021001 nanoscience & nanotechnology, Magnetic Resonance Imaging, 030104 developmental biology, Palmitoyl-CoA Hydrolase, Drug screening, Screening, Calcium, Drosophila, lcsh:Q, 0210 nano-technology |
| الوصف: | 13 p.-9 fig.-1 tab. Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speedingthe identification of modulators of biological targets. However, the exchange chemistriestypically take place under specific reaction conditions, with limited tools capable of operatingunder physiological parameters. Here we report a catalyzed protein-directed DCC working atlow temperatures that allows the calcium sensor NCS-1 tofind the best ligands in situ.Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracingthe molecular assemblies and getting a real-time insight into the essence of DCC processesat physiological pH. Additionally, NMR, X-ray crystallography and computational methods areemployed to elucidate structural and mechanistic aspects of the molecular recognition event.The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8acomplex and whose therapeutic potential is proven in aDrosophilamodel of disease withsynaptic alterations. This work was supported by differentfunding agencies: the Spanish Ministry of Economy and Competitiveness (MINECO)with Grants CTQ2015-69643-R (R.P.F), SAF2015-74507-JIN (A. Mansilla) andBIO2017-89523-R (M.J.S.-B.), and European Cooperation in Science and Technology(COST) action CMI304 Emergence and evolution of complex chemical systems (R.P.-F.),and a 2017 Leonardo Grant for Researchers and Cultural Creators from the BBVAFoundation (M.J.S.-B) and a 2018 CaixaImpulse program from La Caixa Foundation(A.Mansilla). M.J.S.-B. was supported by a Ramón y Cajal Contract RYC-2008-03449from MINECO. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c7679ce5725584876f93eee9255e5b0Test http://link.springer.com/article/10.1038/s41467-019-10627-wTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3c7679ce5725584876f93eee9255e5b0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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