English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/165288
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

Interference of the complex between NCS-1 & Ric8a with phenothiazines regulates synaptic function & is an approach for fragile X syndrome

AuthorsMansilla, Alicia ; Chaves Sanjuán, Antonio; Campillo, Nuria E. ; Semelidou, O.; Martínez-González, L.; Infantes, L. ; Gonzalez-Rubio, Juana M.; Gil, Carmen ; Conde, Santiago ; Skoulakis, E.M.C.; Ferrús, Alberto ; Martínez, Ana ; Sánchez-Barrena, María José
Issue Date2017
CitationProceedings of the National Academy of Sciences of the United States of America 114: E999- E1008 (2017)
AbstractThe protein complex formed by the Ca2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure- function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-Terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.
URIhttp://hdl.handle.net/10261/165288
Identifiersdoi: 10.1073/pnas.1611089114
issn: 1091-6490
Appears in Collections:(CIB) Artículos
(IQFR) Artículos
(IC) Artículos
(IQM) Artículos
Files in This Item:
File Description SizeFormat 
accesoRestringido.pdf15,38 kBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.