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The importance of thermostability and its application to the structure determination of GPCRs

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Structural studies of G protein-coupled receptors (GPCRs) are hampered by their lack of stability in detergents and their conformational flexibility. We have developed a mutagenic strategy combined with a radioligand binding assay to isolate thermostable mutants of GPC Rs biased towards specific conformations. This has allowed us to determine the structures of the b1-adrenergic receptor, adenosine A2A receptor and neurotensin receptor bound to either agonists, partial agonists, inverse agonists or biased agonists. In addition, structures of the adenosine A2A receptor were determined that were used to develop preclinical candidates for the treatment of Parkinson’s disease. I will discuss the strategies used for thermostabilisation, expression and crystallisation, and highlight a few of the biological insights into mechanism revealed by the GPCR structures.

This talk is part of the Experimental and Computational Aspects of Structural Biology and Applications to Drug Discovery series.

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