title: Structure of the adenosine A(2A) receptor bound to an engineered G protein.
abstract: 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. Here we present the structure of the adenosine A(2A) receptor (A(2A)R) bound to an engineered G protein, mini-Gs, at 3.4 Å resolution. Mini-Gs binds to A(2A)R through an extensive interface (1,048 Å2) that is similar, but not identical, to the interface between Gs and the β2-adrenergic receptor. The transition of the receptor from an agonist-bound active-intermediate state to an active G-protein-bound state is characterized by a 14 Å 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 Arg3.50, Tyr5.58 and Tyr7.53. There are no substantial differences in the extracellular half of the receptor around the ligand binding pocket. The A(2A)R-mini-Gs structure highlights both the diversity and similarity in G-protein coupling to GPCRs and hints at the potential complexity of the molecular basis for G-protein specificity.
authors.forename: Byron
authors.initials: B
authors.lastname: Carpenter
authors.forename: Rony
authors.initials: R
authors.lastname: Nehmé
authors.forename: Tony
authors.initials: T
authors.lastname: Warne
authors.forename: Andrew G W
authors.initials: AG
authors.lastname: Leslie
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Tate
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D058908:Adenosine A2 Receptor Agonists; D008024:Ligands; D043705:Receptor, Adenosine A2A; D018343:Receptors, Adrenergic, beta-2; D020962:Heterotrimeric GTP-Binding Proteins