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

Jie Yin, Kuang-Yui M. Chen, Mary J. Clark, Mahdi Hijazi, Punita Kumari, Xiao-chen Bai, Roger K. Sunahara (), Patrick Barth () and Daniel M. Rosenbaum ()
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Jie Yin: The University of Texas Southwestern Medical Center
Kuang-Yui M. Chen: Swiss Federal Institute of Technology (EPFL)
Mary J. Clark: University of California San Diego School of Medicine
Mahdi Hijazi: Swiss Federal Institute of Technology (EPFL)
Punita Kumari: The University of Texas Southwestern Medical Center
Xiao-chen Bai: The University of Texas Southwestern Medical Center
Roger K. Sunahara: University of California San Diego School of Medicine
Patrick Barth: Swiss Federal Institute of Technology (EPFL)
Daniel M. Rosenbaum: The University of Texas Southwestern Medical Center

Nature, 2020, vol. 584, issue 7819, 125-129

Abstract: Abstract The D2 dopamine receptor (DRD2) is a therapeutic target for Parkinson’s disease1 and antipsychotic drugs2. DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine3, leading to stimulation of Gi and inhibition of adenylyl cyclase. Here we used cryo-electron microscopy to elucidate the structure of an agonist-bound activated DRD2–Gi 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 Gi-binding site. The DRD2–Gi 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.

Date: 2020
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DOI: 10.1038/s41586-020-2379-5

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