5G08

Crystal structure of Drosophila NCS-1 bound to chlorpromazine

5G08 の概要

• エントリーDOI: 10.2210/pdb5g08/pdb
• 関連するPDBエントリー: 5FYX
• 分子名称: FREQUENIN 2, CALCIUM ION, 3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethylpropan-1-amine, ... (6 entities in total)
• 機能のキーワード: signaling protein, calcium sensor
• 由来する生物種: DROSOPHILA MELANOGASTER (FRUIT FLY)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22607.80

構造登録者

Chaves-Sanjuan, A.,Infantes, L.,Sanchez-Barrena, M.J. (登録日: 2016-03-17, 公開日: 2017-01-25, 最終更新日: 2024-01-31)

主引用文献

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.
Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome.
Proc. Natl. Acad. Sci. U.S.A., 114:E999-E1008, 2017

PubMed Abstract: The protein complex formed by the Ca 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.

PubMed: 28119500
DOI: 10.1073/pnas.1611089114

実験手法

X-RAY DIFFRACTION (1.52 Å)