In my past work, I have defined the binding of 5-HT to the 5-HT3A receptor, a pentameric ligand-gated ion channel (LGIC). I am currently working on another ligand-gated ion channel, the GABAA receptor. The structure of the GABAA receptor has not been experimentally determined, so together with Kenji Mizuguchi (National Institute of Biomedical Innovation, Osaka), Younes Mokrab, Vassiliy Bavro (Department of Biochemistry, University of Cambridge) and Nikolay Todorov (De Novo Pharmaceuticals, Ltd., Cambridge), I have created comparative models of the GABAA receptor [see diagram on right]. In collaboration with Ian Martin (Department of Pharmacology, Aston University, Birmingham), Susan Dunn (Department of Pharmacology, University of Alberta, Edmonton), S.L. Chan (Chemical Computing Group, Montreal), I have validated these models against published experimental results. I am also planning electron paramagnetic resonance experiments with C.W.M. Kay (Department of Biology, University College, London) to produce distance constraints for further validation of our model.
Once validated, it will be used in simulations to explore the mechanism of ion pore opening in response to ligand binding. I am making a preliminary study of applying Fourier-transform infrared spectroscopy experiments experiments to define the movement of the protein when the ion pore opens, in collaboration with Liang Kuo-Kan (Research Centre for Applied Sciences, Academia Sinica, Taipei).
