6vms
From Proteopedia
Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane
Structural highlights
Function[GNAI1_RAT] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[2] Publication Abstract from PubMedThe D2 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 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. Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane.,Yin J, Chen KM, Clark MJ, Hijazi M, Kumari P, Bai XC, Sunahara RK, Barth P, Rosenbaum DM Nature. 2020 Jun 11. pii: 10.1038/s41586-020-2379-5. doi:, 10.1038/s41586-020-2379-5. PMID:32528175[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Buffalo rat | Human | Large Structures | Lysozyme | Bai, X | Barth, P | Chen, K M | Clark, M J | Hijazi, M | Kumari, P | Rosenbaum, D M | Sunahara, R K | Yin, J | Dopamine | Dopamine receptor | G protein | Gpcr | Parkinson's disease | Signaling protein
