Mechanistic studies of essential membrane transporters

Membrane transporters are essential for cellular life and are generally understudied compared to other membrane proteins, such as GPCR and ion channels. The long-term goal is to pursue a fundamental mechanistic understanding of membrane transporters closely related to human diseases. In this proposal, the overall objective is to extend our previous research on members of human SLC and bacterial siderophore ABC importers. The rationale is that, with detailed knowledge about the structure-function relationship of these membrane transporters, it will be possible to design small molecules explicitly targeting them to have physiological effects. To accomplish the goal, we expect to pursue the following three projects: 1) understanding the substrate selectivity and promiscuity; 2) probing the connection between transporters’ unique structural features and their function; and 3) searching for small molecule inhibitors/activators of the transporters. The approach involved in this proposal is multidisciplinary, including biochemistry, structural biology, microbiology, cell biology, molecular dynamics simulation, and various methodologies of biophysics. This proposal is significant because it is expected to reveal the basic molecular mechanisms of essential membrane transporters and provide scientific justification for further development of drugs targeting these transporters.