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PDBsum entry 6vms
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Signaling protein
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PDB id
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6vms
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Contents |
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227 a.a.
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339 a.a.
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59 a.a.
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232 a.a.
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278 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of a d2 dopamine receptor-G-Protein complex in a lipid membrane.
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Authors
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J.Yin,
K.M.Chen,
M.J.Clark,
M.Hijazi,
P.Kumari,
X.C.Bai,
R.K.Sunahara,
P.Barth,
D.M.Rosenbaum.
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Ref.
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Nature, 2020,
584,
125-129.
[DOI no: ]
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PubMed id
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Abstract
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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.
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