Interference of the complex between NCS-1 & Ric8a with phenothiazines regulates synaptic function & is an approach for fragile X syndrome
Articolo
Data di Pubblicazione:
2017
Citazione:
Interference of the complex between NCS-1 & Ric8a with phenothiazines regulates synaptic function & is an approach for fragile X syndrome / A. Mansilla, A. Chaves-Sanjuan, N.E. Campillo, O. Semelidou, L. Martinez-Gonzalez, L. Infantes, J.M. Gonzalez-Rubio, C. Gil, S. Conde, E.M.C. Skoulakis, A. Ferrus, A. Martinez, M.J. Sanchez-Barrena. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 114:6(2017 Feb 07), pp. E999-e1008. [10.1073/pnas.1611089114]
Abstract:
The 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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Fragile x syndrome; NCS-1; Protein-protein interaction inhibitor; Synapse regulation; X-ray crystallography; Amino Acid Sequence; Animals; Antipsychotic Agents; Crystallography, X-Ray; Disease Models, Animal; Drosophila Proteins; Drosophila melanogaster; Fragile X Syndrome; Guanine Nucleotide Exchange Factors; Humans; Models, Molecular; Molecular Structure; Neuronal Calcium-Sensor Proteins; Neuropeptides; Phenothiazines; Protein Binding; Protein Domains; Sequence Homology, Amino Acid; Synapses
Elenco autori:
A. Mansilla, A. Chaves-Sanjuan, N.E. Campillo, O. Semelidou, L. Martinez-Gonzalez, L. Infantes, J.M. Gonzalez-Rubio, C. Gil, S. Conde, E.M.C. Skoulakis, A. Ferrus, A. Martinez, M.J. Sanchez-Barrena
Link alla scheda completa:
Link al Full Text: