Journal
CELL
Volume 147, Issue 1, Pages 199-208Publisher
CELL PRESS
DOI: 10.1016/j.cell.2011.07.046
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NIBIB NIH HHS [P30 EB009998] Funding Source: Medline
- NIGMS NIH HHS [R01 GM043949, R01 GM043949-21] Funding Source: Medline
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G protein-gated K+ channels (Kir3.1-Kir3.4) control electrical excitability in many different cells. Among their functions relevant to human physiology and disease, they regulate the heart rate and govern a wide range of neuronal activities. Here, we present the first crystal structures of a G protein-gated K+ channel. By comparing the wild-type structure to that of a constitutively active mutant, we identify a global conformational change through which G proteins could open a G loop gate in the cytoplasmic domain. The structures of both channels in the absence and presence of PIP2 suggest that G proteins open only the G loop gate in the absence of PIP2, but in the presence of PIP2 the G loop gate and a second inner helix gate become coupled, so that both gates open. We also identify a strategically located Na+ ion-binding site, which would allow intracellular Na+ to modulate GIRK channel activity. These data provide a structural basis for understanding multiligand regulation of GIRK channel gating.
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