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:

• (1) They are difficult to over express and purify.
• (2) They are difficult to crystallize because of their hydrophobicity.
• (3) That in turn makes it difficult to obtain good X ray diffraction data.

Structure determination of human GPCR β2 adrenergic receptor by Dr. Stevens of Scripps Institute and Prof. Kobilka of Stanford in 2007 will no doubt add impetus to the structural study of human GPCR. This project aims to tackle all these challenges in order to establish a methodology for determining 3D structure of human membrane receptors systematically, capitalizing on the know-how Prof. So Iwata, the Research Director, has accumulated over the years solving structure of non-human membrane proteins. Research strategies are:

• (1)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
• (2) to design binders which bind to these receptors, and increase hydrophilicity and crystallizabillity
• (3) 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.
• (4) to construct a low-noise data analysis system using a next generation beam line

The results of the project will have broad applications in life sciences, such as identifying various signal transduction passways in a cell, not limited in drug design.

Prof. So Iwata, the Research Director, conducts his research both in the UK and in Japan. His main research group is Membrane Protein Crystallography (MPC) Group of Imperial College London, UK. The group has another research lab at a synchrotron radiation facility Diamond where he holds the position of Diamond Fellow. Prof. Iwata currently holds positions of director of Centre for Structural Biology and David Blow Chair of Biophysics at Department of Life Sciences, Imperial College London. His another research group is Cell Biology Laboratory of Graduate School of Medicine, Kyoto University in Japan. The project is funded by ERATO (Exploratory Research for Advanced Technology), JST (Japan Science and Technology Agency), and it has research sites at Diamond in the UK and at Kyoto University in Japan. The project will enjoy cooperation with Diamond, MPC group, and Centre for Structural Biology at Imperial College London in the UK, as well as Cell Biology Laboratory at Kyoto University and Protein Research Group, RIKEN Yokohama Institute.
more detailed info (in Japanese)