Understanding membrane transporters through their atomic structures
Since proteins have to change their three-dimensional structures to achieve their functions, it is impossible to understand how they work without knowing their 3D structures. We aim at understanding the functions of important proteins based on the atomic structures using X-ray crystallography as the principal tool. We focus on the structural basis of active ion transport and have already succeeded in determining the atomic structures for 10 different states that nearly cover the entire reaction cycle of the calcium pump (3). As a result, we now roughly understand how ion pumps work and can answer fundamental questions, e.g. what ATP and phosphorylation do. Crystal structures represent, however, only a few points in the reaction cycle and protons, which play important roles in structural changes and functions, are invisible to X-ray. Therefore, theoretical calculations are also important in our study. We have also established an expression system using mammalian cell culture and succeeded in crystal structure analysis of a mutant. Such technology is unique and will become more and more important. Another principal target of our study, in collaboration with a Danish group, is the sodium pump (2, 4), which is expressed in all animal cells and deeply implicated in many diseases.
These results have been recognized world-wide and Prof. Toyoshima was elected to prestigious Foreign Associate of the National Academy of Science, U.S.A. and a Hitchcock Professor at UC Barkeley. His lectures and interview can be seen on YouTube. He was also awarded a Medal with Purple Ribbon in 2015, Gregori Aminoff Prize in 2016 and the Imperial and Japan Academy Prizes in 2018.