TY - JOUR
T1 - Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium
AU - Whorton, Matthew R.
AU - MacKinnon, Roderick
PY - 2011/9/30
Y1 - 2011/9/30
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=80053485088&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053485088&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.07.046
DO - 10.1016/j.cell.2011.07.046
M3 - Article
C2 - 21962516
AN - SCOPUS:80053485088
SN - 0092-8674
VL - 147
SP - 199
EP - 208
JO - Cell
JF - Cell
IS - 1
ER -