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TitleStructure of a D2 dopamine receptor-G-protein complex in a lipid membrane.
Journal, issue, pagesNature, Vol. 584, Issue 7819, Page 125-129, Year 2020
Publish dateJun 11, 2020
AuthorsJie Yin / Kuang-Yui M Chen / Mary J Clark / Mahdi Hijazi / Punita Kumari / Xiao-Chen Bai / Roger K Sunahara / Patrick Barth / Daniel M Rosenbaum /
PubMed AbstractThe 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 ...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.
External linksNature / PubMed:32528175 / PubMed Central
MethodsEM (single particle)
Resolution3.7 - 3.8 Å
Structure data

EMDB-21243, PDB-6vms:
Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-21244:
Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-21245:
Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-08Y:
bromoergocryptine / agonist*YM / Bromocriptine

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • enterobacteria phage t4 (virus)
KeywordsSIGNALING PROTEIN / Dopamine / Dopamine receptor / GPCR / G protein / Parkinson's disease

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