3D structure of brain receptors
Transmission of information from and to the brain occurs through neurons, specialised cells capable of transmitting signals using specific neurotransmitters. These neurotransmitters (also called ligands) are received on CLRs to regulate signal transduction. CLRs thus constitute molecular targets for various drugs, and their dysfunction has been linked with various neurological, muscle and psychiatric diseases. In spite of their important role in signal transmission, little is known about the 3D structure of CLRs. With this in mind, the EU-funded 'Neurotransmitter Cys-loop receptors: Structure, function and disease' (NEUROCYPRES) project was designed to provide high-resolution information on the 3D structure of CLRs. The long-term goal was to utilise crystallisation data of various receptors with neurotransmitters for pharmaceutical drug design. Despite their functional heterogeneity, CLRs have similar protein architecture and as a result the structural information obtained could be extrapolated to other CLR types. High-throughput robotics were developed for the crystallisation of small amounts of protein that could subsequently be analysed to unravel the CLR structures. Additionally, CLR functional domains were determined by obtaining crystal complexes with diverse ligands and agonists/antagonists. Computer modelling further allowed the studying of ligand–receptor interaction and led to the discovery of novel compounds with high CLR affinity. In order to study the physiological role of CLRs in the brain, genetic models were developed that enabled the visualisation of receptor activity and activation state. New mutations in the genes encoding for the neuronal nicotinic acetylcholine receptors helped link these genes to a form of epilepsy, thus opening up new avenues for drug design. NEUROCYPRES activities with regard to CLR structure and function, will eventually lead to the development of targeted therapy for specific CLR ligands. Besides reducing any adverse effects of drug cross-reactivity, effective personalised medicine is a step closer to realisation.
Keywords
Cys-loop receptor, neurotransmitter receptor, crystallisation, ligands, molecular target, cross-reactivity
