Structure of the adenosine A2A receptor bound to an engineered G protein

G-protein-coupled receptors (GPCRs) are essential components of the signalling network throughout the body. To understand the molecular mechanism of G-protein-mediated signalling, solved structures of receptors in inactive conformations and in the active conformation coupled to a G protein are necessary(1,2). Here we present the structure of the adenosine A(2A) receptor (A(2A)R) bound to an engineered G protein, mini-G(s), at 3.4 angstrom resolution. Mini-G(s) binds to A(2A)R through an extensive interface (1,048 angstrom(2)) that is similar, but not identical, to the interface between G(s) and the beta(2)-adrenergic receptor(3). The transition of the receptor from an agonist-bound active-intermediate state(4,5) to an active G-protein-bound state is characterized by a 14 angstrom shift of the cytoplasmic end of transmembrane helix 6 (H6) away from the receptor core, slight changes in the positions of the cytoplasmic ends of H5 and H7 and rotamer changes of the amino acid side chains Arg(3.50), Tyr(5.58) and Tyr(7.53). There are no substantial differences in the extracellular half of the receptor around the ligand binding pocket. The A(2A)R-mini-G(s) structure highlights both the diversity and similarity in G-protein coupling to GPCRs(6) and hints at the potential complexity of the molecular basis for G-protein specificity.