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Neurotransmitter Cys-loop receptors: structure, function and disease

Objective

Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimer’s and Parkinson’s, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function. A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.

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Call for proposal

FP7-HEALTH-2007-A
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Funding Scheme

CP-IP - Large-scale integrating project

Coordinator

STICHTING VU
EU contribution
No data
Address
DE BOELELAAN 1105
1081 HV Amsterdam
Netherlands

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Region
West-Nederland Noord-Holland Groot-Amsterdam
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Yvonne Kops (Dr.)
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Total cost
No data

Participants (23)

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Last update: 5 April 2023

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Permalink: https://cordis.europa.eu/project/id/202088

European Union, 2024