Structure of the adenosine A2A receptor bound to an engineered G protein
| Autor: | Christopher G. Tate, Rony Nehmé, Tony Warne, Andrew G. W. Leslie, Byron Carpenter |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Cytoplasm Adenosine A2 Receptor Agonists Receptor Adenosine A2A G protein Protein Conformation Molecular Sequence Data Adenosine A2A receptor Biology Crystallography X-Ray Ligands Article Substrate Specificity 03 medical and health sciences 0302 clinical medicine Protein structure Humans Amino Acid Sequence Binding site Receptor Peptide sequence G protein-coupled receptor Multidisciplinary Binding Sites Heterotrimeric GTP-Binding Proteins Transmembrane domain 030104 developmental biology Biochemistry Biophysics Receptors Adrenergic beta-2 Crystallization 030217 neurology & neurosurgery |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | An engineered G protein is used to bind to and stabilize the active conformation of the adenosine A2A receptor, enabling the acquisition of an X-ray crystal structure of this GPCR in an active state. G-protein-coupled receptors (GPCRs) are essential components of signalling networks throughout the body, and about a third of all clinical drugs target GPCRs. The X-ray structures of GPCRs in an active conformation have proved elusive. This paper describes the crystal structure of adenosine A2A receptor bound to a G protein, which represents the first X-ray structure of the fully active state of the receptor. The trick used here involved engineering a G protein — termed mini-Gs — that binds to and stabilizes the active state of the adenosine A2A receptor. The hope is that this mini-Gs will facilitate the crystallization and characterization of other Gs-coupled GPCRs in their active states. 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 necessary1,2. Here we present the structure of the adenosine A2A receptor (A2AR) bound to an engineered G protein, mini-Gs, at 3.4 A resolution. Mini-Gs binds to A2AR through an extensive interface (1,048 A2) that is similar, but not identical, to the interface between Gs and the β2-adrenergic receptor3. The transition of the receptor from an agonist-bound active-intermediate state4,5 to an active G-protein-bound state is characterized by a 14 A 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 A2AR–mini-Gs structure highlights both the diversity and similarity in G-protein coupling to GPCRs6 and hints at the potential complexity of the molecular basis for G-protein specificity. |
| Databáze: | OpenAIRE |
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