G protein-coupled receptors (GPCRs) activate intracellular signalling proteins (G proteins and arrestins) in response to extracellular signalling molecules. GPCRs are highly dynamic proteins, which rapidly interchange between different conformational states. In order to understand the molecular mechanisms of GPCR activation, structures of GPCRs in different conformational states are required.
We have determined structures of the adenosine A_2a receptor (A_2aR) and b₁ adrenoceptor (b₁AR) in a variety of different states bound to ligands ranging from inverse agonists to full agonists. Structures in active states have also been determined of A_2aR and the serotonin 5-HT_1B receptor coupled to the heterotrimeric G proteins G_s and G_o, respectively. I will use this wealth of structural data to address a number of questions with respect to GPCR pharmacology such as why G proteins cause an increase in agonist affinity and what are the factors that affect the specificity of G protein coupling.

1. García-Nafría, J., Lee, Y., Bai, X., Carpenter, B. & Tate, C.G. (2018) Cryo-EM structure of the adenosine A_2A receptor coupled to an engineered heterotrimeric G protein. eLife 7, e35946
2. García-Nafría, J., Nehmé, R., Edwards, P.C. & Tate, C.G. (2018) Cryo-EM structure of the serotonin 5-HT_1B receptor coupled to heterotrimeric G_o. Nature, In press.
3. Warne, T., Edwards, P.C. Doré, A.S., Leslie, A.G.W. & Tate, C.G. (2018) Molecular diversity of high affinity agonist binding in active states of the β₁-adrenoceptor. Submitted.