Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.

Publication Type:

Journal Article


Cell, Volume 147, Issue 1, p.199-208 (2011)


Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, G Protein-Coupled Inwardly-Rectifying Potassium Channels, GTP-Binding Proteins, Humans, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Phosphatidylinositol 4,5-Diphosphate, Sequence Alignment, Sodium, Xenopus laevis


<p>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 PIP(2) suggest that G proteins open only the G loop gate in the absence of PIP(2), but in the presence of PIP(2) 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.</p>