Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal
| Autor: | Gregorio Valencia, Ana Gimeno, Mobina Alemi, Jordi Llop, Isabel Cardoso, Gemma Arsequell, Daniel Blasi, Luis Miguel Santos, Jesús Jiménez-Barbero, Ellen Y. Cotrina, Jordi Quintana, Josep Rivas |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
endocrine system Magnetic Resonance Spectroscopy transthyretin Molecular model (−)-epigallocatechin gallate Peptide Crystallography X-Ray 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Humans Prealbumin Protein Interaction Maps iododiflunisal Ternary complex TTR amyloidosis chemistry.chemical_classification Amyloid beta-Peptides biology Chemistry Iododiflunisal Spectroscopy methods nutritional and metabolic diseases Amyloidosis Diflunisal medicine.disease Molecular Docking Simulation Transthyretin STD NMR 030104 developmental biology Biochemistry Saturation transfer biology.protein Molecular Medicine Alzheimer's disease Alzheimer disease 030217 neurology & neurosurgery |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Several strategies against Alzheimer disease (AD) are directed to target Aβ-peptides. The ability of transthyretin (TTR) to bind Aβ-peptides and the positive effect exerted by some TTR stabilizers for modulating the TTR-Aβ interaction have been previously studied. Herein, key structural features of the interaction between TTR and the Aβ(12-28) peptide (3), the essential recognition element of Aβ, have been unravelled by STD-NMR spectroscopy methods in solution. Molecular aspects related to the role of the TTR stabilizer iododiflunisal (IDIF, 5) on the TTR-Aβ complex have been also examined. The NMR results, assisted by molecular modeling protocols, have provided a structural model for the TTR-Aβ interaction, as well as for the ternary complex formed in the presence of IDIF. This basic structural information could be relevant for providing light on the mechanisms involved in the ameliorating effects of AD symptoms observed in AD/TTR± animal models after IDIF treatment and eventually for designing new molecules toward AD therapeutic drugs. © 2017 American Chemical Society. The work was supported by a grant from the FundacióMarató de TV3 (Neurodegenerative Diseases Call, Project Reference 20140330-31-32-33-34, http://www.ccma.cat/tv3/marato/en/ projectes-financats/2013/212/). The group at CIC bioGUNE also acknowledges MINECO (Spain) for funding through Grant CTQ2015-64597-C2-1-P and a Juan de la Cierva contract to A.G. The group at IBMC-i3S also acknowledges funding through Grant Norte-01-0145-FEDER-000008-Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). I.C. works under the Investigator FCT Program which is financed by national funds through FCT and cofinanced by ESF through HPOP, Type 4.2, Promotion of Scientific Employment. M.A. is currently a recipient of a Research Fellowship (BIM) funded by the project of FundacióMarató de TV3, Spain, and L.M.S. is currently a recipient of a fellowship from Norte 2020. IQAC-CSIC acknowledges a contract to E.Y.C. funded by the project of FundacióMaratóde TV3, Spain. |
| Databáze: | OpenAIRE |
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