Cys-loop neurotransmitter receptors: molecular mechanisms underlying function. (360G-Wellcome-081925_Z_07_A)

The aim of this project is to define the structural basis of the mechanism of action of the Cys loop family of neurotransmitter receptors. The roles and specific chemical interactions of amino acid residues in both 5-HT3 and GABAc receptor binding sites, and in the protein subdomains that link and drive channel opening, will be characterised, using both theoretical (modelling, docking, molecular dynamics) and experimental approaches (mutagenesis, radioligand binding, functional assays, fluoresce nce measurements, structure determination). The key goals are defining (a) the molecular interactions that are critical for the binding of 5-HT or GABA and other agonists and antagonists; (b) the molecular interactions in the binding site that initiate receptor gating; (c) the conformational changes that occur in the extracellular ligand-binding site as a result of agonist binding; (d) how these changes are transduced to the pore lining M2 domain; and (e) how M2 moves to open the channel.