Structure of a D(2) dopamine receptor-G protein complex in a lipid membrane

The D(2) dopamine receptor (DRD2) is a therapeutic target for Parkinson’s disease(1) and antipsychotic drugs(2). DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine(3), leading to stimulation of G(i) and inhibition of adenylyl cyclase. We used cryo-electron microscopy to elucidate the structure of an agonist-bound activated DRD2-G(i) complex reconstituted into a phospholipid membrane. The extracellular ligand binding site of DRD2 is remodeled in response to agonist binding, with conformational changes in extracellular loop 2 (ECL2), transmembrane domain 5 (TM5), TM6, and TM7 propagating to opening of the intracellular G(i) binding site. The DRD2-G(i) structure represents the first experimental model of a GPCR-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 sidechains in the membrane interfacial regions, and lipid anchoring of the G protein in the membrane. Our model of the activated DRD2 will help inform the design of subtype-selective DRD2 ligands for multiple human CNS disorders.