Download MendeleyInterference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome.
Mansilla, A., Chaves-Sanjuan, A., Campillo, N.E., Semelidou, O., Martinez-Gonzalez, L., Infantes, L., Gonzalez-Rubio, J.M., Gil, C., Conde, S., Skoulakis, E.M., Ferrus, A., Martinez, A., Sanchez-Barrena, M.J.(2017) Proc Natl Acad Sci U S A 114: E999-E1008
- PubMed: 28119500
- DOI: https://doi.org/10.1073/pnas.1611089114
- Primary Citation of Related Structures:
5AAN, 5FYX, 5G08 - PubMed Abstract:
The protein complex formed by the Ca 2+ 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.
Organizational Affiliation:
Departamento de Neurobiología del Desarrollo, Instituto Cajal, Spanish National Research Council, 28002 Madrid, Spain.
