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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.
Identifiersdoi: 10.1073/pnas.1611089114
issn: 1091-6490
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