The molecular mechanism by which PIP(2) opens the intracellular G-loop gate of a Kir3.1 channel

Biophys J. 2012 May 2;102(9):2049-59. doi: 10.1016/j.bpj.2012.03.050.


Inwardly rectifying potassium (Kir) channels are characterized by a long pore comprised of continuous transmembrane and cytosolic portions. A high-resolution structure of a Kir3.1 chimera revealed the presence of the cytosolic (G-loop) gate captured in the closed or open conformations. Here, we conducted molecular-dynamics simulations of these two channel states in the presence and absence of phosphatidylinositol bisphosphate (PIP(2)), a phospholipid that is known to gate Kir channels. Simulations of the closed state with PIP(2) revealed an intermediate state between the closed and open conformations involving direct transient interactions with PIP(2), as well as a network of transitional inter- and intrasubunit interactions. Key elements in the G-loop gating transition involved a PIP(2)-driven movement of the N-terminus and C-linker that removed constraining intermolecular interactions and led to CD-loop stabilization of the G-loop gate in the open state. To our knowledge, this is the first dynamic molecular view of PIP(2)-induced channel gating that is consistent with existing experimental data.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / chemistry*
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / ultrastructure*
  • Intracellular Space
  • Ion Channel Gating*
  • Models, Chemical*
  • Models, Molecular*
  • Phosphatidylinositol 4,5-Diphosphate / chemistry*
  • Porosity
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary


  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Phosphatidylinositol 4,5-Diphosphate