6VMS

Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane

Summary for 6VMS

• Entry DOI: 10.2210/pdb6vms/pdb
• EMDB information: 21243
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: dopamine, dopamine receptor, gpcr, g protein, parkinson's disease, signaling protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 5
• Total formula weight: 166760.00

Authors

Yin, J.,Chen, K.M.,Clark, M.J.,Hijazi, M.,Kumari, P.,Bai, X.,Sunahara, R.K.,Barth, P.,Rosenbaum, D.M. (deposition date: 2020-01-28, release date: 2020-06-17, Last modification date: 2024-10-23)

Primary citation

Yin, J.,Chen, K.M.,Clark, M.J.,Hijazi, M.,Kumari, P.,Bai, X.C.,Sunahara, R.K.,Barth, P.,Rosenbaum, D.M.
Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane.
Nature, 584:125-129, 2020

PubMed Abstract: 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.

PubMed: 32528175
DOI: 10.1038/s41586-020-2379-5

Experimental method

ELECTRON MICROSCOPY (3.8 Å)