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Class B G-Protein-Coupled Receptor Structure Solved by Cryo-EM

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In a paper published today in the influential journal Nature, researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) at Monash University discuss the use of a novel technique to reveal the structure of an important drug target. The new research provides a deeper understanding of how the target functions, opening the way for the creation of more advanced drugs with fewer side effects.

Treatments for chronic diseases including osteoporosis, diabetes and obesity all target Class B G protein-coupled-receptors.

Unfortunately there are large gaps in our knowledge of how these receptors function. In part, this stems from their size.  They are so small that only in the past few years has technology advanced to a stage where researchers are beginning to be able to “solve the structure” – to attain an understanding of what these receptors look like.

This is important because knowing how the receptors are structured helps us understand how they work. This knowledge in turn can enable the design of drugs that target the receptor more accurately and have fewer side effects.

The structure solved by the MIPS researchers and their collaborators is that of the calcitonin receptor, a receptor targeted by treatments for hypercalcemia and Paget’s disease (a bone disorder). The breakthrough is significant not just because of the additional knowledge it reveals, but also because of the method used to uncover it. This is the first time that a cryo-electron microscope has been used to reveal the structure of a G protein-coupled-receptor. It is also the first time that the full-length structure of a receptor in this class has been solved, and in a form that allows the structure to be linked to its beneficial effects.

“The fact that we have been able to use cryo-electron microscopy to arrive at these important findings is a vindication of investment to date in this area, and makes a strong case for further investment in the future,” said Doctor Denise Wootten, Group Leader, Class B GPCR Biology at MIPS.

“The information revealed by this study should ultimately enable the design of better drugs to treat not only diseases regulated by the calcitonin receptor but also those involving related receptors including diabetes, obesity, osteoporosis and migraine” said Professor Patrick Sexton, Head of Drug Discovery Biology at MIPS.

Liang, Y., Khoshouei, M., Radjainia, M., Zhang, Y., Glukhova, A., Tarrasch, J., Thal, D., Furness, S., Christopoulos, G., Coudrat, T., Danev, R., Baumeister, W., Miller, L., Christopoulos, A., Kobilka, B., Wootten, D., Skiniotis, G. and Sexton, P. (2017). Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature.

This article has been republished from materials provided by Monash University. Note: material may have been edited for length and content. For further information, please contact the cited source.