Nature (London), 2020-08, Vol.584 (7819), p.125-129
2020
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane
- Ist Teil von
- Nature (London), 2020-08, Vol.584 (7819), p.125-129
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The D2 dopamine receptor (DRD2) is a therapeutic target for Parkinson's disease and antipsychotic drugs . DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine , leading to stimulation of G and inhibition of adenylyl cyclase. Here we used cryo-electron microscopy to elucidate the structure of an agonist-bound activated DRD2-G complex reconstituted into a phospholipid membrane. The extracellular ligand-binding site of DRD2 is remodelled in response to agonist binding, with conformational changes in extracellular loop 2, transmembrane domain 5 (TM5), TM6 and TM7, propagating to opening of the intracellular G -binding site. The DRD2-G structure represents, to our knowledge, the first experimental model of a G-protein-coupled receptor-G-protein complex embedded in a phospholipid bilayer, which serves as a benchmark to validate the interactions seen in previous detergent-bound structures. The structure also reveals interactions that are unique to the membrane-embedded complex, including helix 8 burial in the inner leaflet, ordered lysine and arginine side chains in the membrane interfacial regions, and lipid anchoring of the G protein in the membrane. Our model of the activated DRD2 will help to inform the design of subtype-selective DRD2 ligands for multiple human central nervous system disorders.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/s41586-020-2379-5Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7415663
- Format
- –
- Schlagworte
- Adenylate cyclase, Agonists, Anchoring, Antipsychotics, Arginine, Binding sites, Bromocriptine - chemistry, Bromocriptine - metabolism, Central nervous system, Cryoelectron Microscopy, Design, Dopamine, Dopamine - chemistry, Dopamine - metabolism, Dopamine D2 receptors, Drug development, Electron microscopy, G protein-coupled receptors, GTP-Binding Protein alpha Subunits, Gi-Go - chemistry, GTP-Binding Protein alpha Subunits, Gi-Go - metabolism, GTP-Binding Protein alpha Subunits, Gi-Go - ultrastructure, Humans, Ligands, Lipids, Lysine, Membrane Lipids - chemistry, Membrane Lipids - metabolism, Membrane proteins, Membranes, Membranes, Artificial, Microscopy, Models, Molecular, Movement disorders, Mutation, Neurodegenerative diseases, Neurotransmitters, Parkinson's disease, Phospholipids, Protein Conformation, Proteins, Receptors, Receptors, Dopamine D2 - agonists, Receptors, Dopamine D2 - chemistry, Receptors, Dopamine D2 - metabolism, Receptors, Dopamine D2 - ultrastructure, Schizophrenia, Signal Transduction