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

被引：29

作者：

Mansilla, Alicia ^{[1
]}

Chaves-Sanjuan, Antonio ^{[2
]}

Campillo, Nuria E. ^{[3
]}

Semelidou, Ourania ^{[4
]}

Martinez-Gonzalez, Loreto ^{[3
]}

Infantes, Lourdes ^{[2
]}

Maria Gonzalez-Rubio, Juana ^{[2
]}

Gil, Carmen ^{[3
]}

Conde, Santiago ^{[5
]}

Skoulakis, Efthimios M. C. ^{[4
]}

Ferrus, Alberto ^{[1
]}

Martinez, Ana ^{[3
]}

Jose Sanchez-Barrena, Maria ^{[2
]}

机构：

[1] Spanish Natl Res Council, Inst Cajal, Dept Neurobiol Desarrollo, Madrid 28002, Spain

[2] Spanish Natl Res Council, Inst Quim Fis Rocasolano, Dept Cristalog & Biol Estruct, Madrid 28006, Spain

[3] Spanish Natl Res Council, Ctr Invest Biol, Madrid 28040, Spain

[4] Biomed Sci Res Ctr Alexander Fleming, Div Neurosci, Vari 16672, Greece

[5] Spanish Natl Res Council, Inst Quim Med, Madrid 28006, Spain

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 06期

关键词：

fragile X syndrome; synapse regulation; NCS-1; protein-protein interaction inhibitor; X-ray crystallography; MENTAL-RETARDATION PROTEIN; NEURONAL CALCIUM SENSOR; IMMUNOCYTOCHEMICAL LOCALIZATION; STRUCTURAL INSIGHTS; BINDING PROPERTIES; CRYSTAL-STRUCTURE; DROSOPHILA; MEMORY; INHIBITION; FMRP;

D O I：

10.1073/pnas.1611089114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：E999 / E1008

页数：10