Structural studies of G protein-coupled receptors 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 GPCRs biased towards specific conformations. This led initially to the structure determination of a thermostabilised avian �1 adrenoceptor mutant (�36-m23) in complex with the antagonist cyanopindolol at 2.7 � resolution. Recently we have determined 8 additional structures of �36-m23 bound to different antagonists and agonists and, in addition, the structures of the adenosine A2A receptor bound to the agonists adenosine and NECA. I will discuss the structural basis for the pharmacological profiles of the ligands and how these structures have illuminated the mechanism of GPCR activation upon agonist binding.

Structural basis for agonism and inverse agonism in the β<sub>1</sub>-adrenoceptor and adenosine A<sub>2A</sub> receptor

243rd National Meeting (2012)

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Structural basis for agonism and inverse agonism in the β1-adrenoceptor and adenosine A2A receptor

Structural basis for agonism and inverse agonism in the β₁-adrenoceptor and adenosine A_2A receptor