X-ray structure of the mammalian GIRK2-βγ G-protein complex

Matthew Whorton, Roderick MacKinnon

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

G-protein-gated inward rectifier K + (GIRK) channels allow neurotransmitters, through G-protein-coupled receptor stimulation, to control cellular electrical excitability. In cardiac and neuronal cells this control regulates heart rate and neural circuit activity, respectively. Here we present the 3.5 Å resolution crystal structure of the mammalian GIRK2 channel in complex with βγ G-protein subunits, the central signalling complex that links G-protein-coupled receptor stimulation to K + channel activity. Short-range atomic and long-range electrostatic interactions stabilize four βγ G-protein subunits at the interfaces between four K + channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed conformation and the open conformation of the constitutively active mutant. The resultant structural picture is compatible with 'membrane delimited' activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signalling lipid phosphatidylinositol-4,5-bisphosphate (PIP 2) and intracellular Na + ions participate in multi-ligand regulation of GIRK channels.

Original languageEnglish (US)
Pages (from-to)190-197
Number of pages8
JournalNature
Volume498
Issue number7453
DOIs
StatePublished - 2013
Externally publishedYes

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GTP-Binding Proteins
X-Rays
Inwardly Rectifying Potassium Channel
Protein Subunits
G-Protein-Coupled Receptors
Phosphatidylinositols
Static Electricity
Neurotransmitter Agents
Heart Rate
Ions
Ligands
Lipids
Membranes

ASJC Scopus subject areas

  • General

Cite this

X-ray structure of the mammalian GIRK2-βγ G-protein complex. / Whorton, Matthew; MacKinnon, Roderick.

In: Nature, Vol. 498, No. 7453, 2013, p. 190-197.

Research output: Contribution to journalArticle

Whorton, Matthew ; MacKinnon, Roderick. / X-ray structure of the mammalian GIRK2-βγ G-protein complex. In: Nature. 2013 ; Vol. 498, No. 7453. pp. 190-197.
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