Mission
Establish a Methodology to Determine 3D Structure of Human GPCRs
Thanks to the Human Genome Project, many disease-causing proteins have been identified during recent years. Once 3D structure of these disease-related proteins are determined, the data can be utilized not only to develop a drug more efficiently, but also to design molecularly more targeted drug with lower side effects. Although more than 50% of commercially available drugs target membrane proteins, most notably
G-protein coupled receptors (GPCRs), none of human GPCR has had its structure determined when this project started in 2006. This is mainly due to the following methodological challenges that are unique to the membrane proteins:
G-protein coupled receptors (GPCRs), none of human GPCR has had its structure determined when this project started in 2006. This is mainly due to the following methodological challenges that are unique to the membrane proteins:
- They are difficult to over express and purify.
- They are difficult to crystallize because of their hydrophobicity.
- That in turn makes it difficult to obtain good X ray diffraction data.
- to develop a yeast-based over expression system for functional membarne receptors,
and a method to remove sacchride chains which interfere with crystallization of these proteins - to design binders which bind to these receptors, and increase hydrophilicity and crystallizabillity
- to implement a high throughput screening system for optimization of crystallizing conditions
by combining a nano-drop crystallization technique and robotic multiple-crystal-mounting system. - to construct a low-noise data analysis system using a next generation beam line