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Beamlines | MX Case Study

Taking control of our vital signal transmitters

G-protein-coupled receptors (GPCRs) are the single most important drug target in the body because they are central to so many biological processes. Gaining a better understanding of how GPCRs operate will help scientists develop novel strategies to modulate their activity, potentially affecting their role in diseases such as Parkinson’s or conditions such as insomnia.

Diamond’s Microfocus Macromolecular Crystallography (MX) beamline I24 has recently been used by a team of scientists from Kyoto University and the University of Tokyo, Japan, to determine the structure of the GPCR A2A adenosine receptor (AR) bound with an antibody fragment that inhibits the protein’s response. Their findings, published in the journal Nature on 29th January, shed light on a novel strategy to modulate GPCR activity.

GPCRs are responsible for transmitting chemical signals into a variety of different cell types. A2AAR has many vital roles, for example, regulating blood flow to the cardiac muscle, and the release of glutamate and dopamine in the brain. Being able to control the effect of neurotransmitters such as these makes A2AAR a potential therapeutic target in conditions such as insomnia, pain, depression and Parkinson’s disease.
 
By solving the structure of A2AAR bound to the antibody fragment, the team was able to understand how the binding mechanism works. 
“An important feature of a GPCR is the intracellular loop 3, it is critical for G-protein binding – the action that triggers the receptor’s response. In previous experiments this loop has been cut out and replaced with an alternative protein to enable crystallisation of the GPCR. But in this study, we successfully crystallised A2AAR with the intracellular loop 3 intact.

“From the data gathered on beamline I24, we were able to see where the loop 3 connects. We could see that the antibody fragment induces an inactive conformation of the receptor and locks it into an inactive state. This is the first time diffraction data has been collected from this receptor with the intracellular loop 3 intact. Having a better understanding of how the GPCR binding mechanism works increases our ability to control GPCR activity. This gives us a better chance to work on treatments for diseases and conditions where GPCRs play a key role.”

Dr Simone Weyand, a post-doctoral scientist at Imperial College London, who was part of the experimental work at Diamond

There are over 700 GPCRs encoded in the human genome and as many as 75 of these have clinical validation, presenting a wide range of opportunities as therapeutic targets in areas including cancer, diabetes, central nervous system disorders, obesity and pain. The design of drugs for GPCRs is hampered by the lack of structural information so access to a facility like the Diamond synchrotron and an instrument like the Microfocus MX beamline, which is capable of studying tiny micro-crystals using an X-ray beam just a few microns wide, is vital to research.

 
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‘G protein-coupled receptor inactivation by an allosteric inverse-agonist antibody’
Tomoya Hino, Takatoshi Arakawa, Hiroko Iwanari, Takami Yurugi-Kobayashi, Chiyo Ikeda-Suno, Yoshiko Nakada-Nakura, Osamu Kusano-Arai, Simone Weyand, Tatsuro Shimamura, Norimichi Nomura, Alexander D. Cameron, Takuya Kobayashi, Takao Hamakubo, So Iwata & Takeshi Murata.
Published online in Nature on 29th January 2012
doi:10.1038/nature10750
 
Acknowledgments

Japan Science and Technology Agency Ministry of Education, Culture, Sports, Science and Technology New Energy and Industrial Technology Development Organization (NEDO) Biotechnology and Biological Sciences Research Council (BBSRC) Wellcome Trust.