Molecular mechanism of phosphoinositides' specificity for the inwardly rectifying potassium channel Kir2.2.

ABSTRACT: Phosphoinositides are essential signaling lipids that play a critical role in regulating ion channels, and their dysregulation often results in fatal diseases including cardiac arrhythmia and paralysis. Despite decades of intensive research, the underlying molecular mechanism of lipid agonism and specificity remains largely unknown. Here, we present a systematic study of the binding mechanism and specificity of a native agonist, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) and two of its variants, PI(3,4)P₂ and PI(3,4,5)P₃, on inwardly rectifying potassium channel Kir2.2, using molecular dynamics simulations and free energy perturbations (FEPs). Our results demonstrate that the major driving force for the PI(4,5)P₂ specificity on Kir2.2 come

SUBMITTER: Meng XY 

PROVIDER: S-EPMC6247517 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature