My main research interest lies in probing the structures of membrane proteins and their complexes, and understanding the molecular basis of their biological functions. My aim is to establish an infrastructure wherein the structure of any membrane protein including its complexes can be investigated in any functional state, i.e. catching molecular machines of cellular membranes in action.
Membrane proteins are involved in various critical biological processes, and account for 70% of all known pharmacological targets. However, only about 200 unique membrane protein structures have been identified bacause of the difficulty in forming crystals for X-ray and electron crystallography.
During my postdoctoral training in Sigworth lab at Yale University, I had been working on the development of a novel and general method, called “random spherically constrained” (RSC) single-particle cryo-EM, to study membrane protein structures in membrane environments. The RSC method has involved the development of new specimen architectures and software algorithms that take advantage of these architectures, and has been successfully applied this method to obtain the structure of the large conductance voltage- and calcium-activated potassium (BK) channel in a lipid membrane, which answered several biologically important questions.
Currently, my research focuses on two kinds of membrane proteins.
- HCN Channel: HCN Hyperpolarization- activated cyclic nucleotide-gated (HCN) channels are widely expressed throughout the nervous system and in the heart. They regulate cardiac and neuronal firing rates (“pacemaker” activity). The determined structures will potentially facilitate the development of new therapeutic agents to treat diseases in broad areas, such as cardiac arrhythmia, and the malfunction of various regions of the brain including the prefrontal cortex.
- BK Channel: BK channels are found in a wide range of tissues (e.g. brain, vascular system) and are involved in the control of a number of cell functions. They contribute to the feedback control of Ca2+ influx and neurotransmission, shaping action potentials, and the frequency adaptation processes in the nervous system. BK channels are expected to be targeted for the therapy of cardiovascular diseases, neuropathies, ischemic stroke and cognitive disorders.