Jump to main content
Jump to site search

Issue 44, 2018
Previous Article Next Article

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

Author affiliations

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 comes from the highly organized salt-bridge network formed between the charged inositol head and phosphodiester linker of PI(4,5)P2. The unsaturated arachidonic chain is also shown to contribute to the stable binding through hydrophobic interactions with nearby Kir2.2 hydrophobic residues. Consistent with previous experimental findings, our FEP results confirmed that non-native ligands, PI(3,4)P2 and PI(3,4,5)P3, show significant loss in binding affinity as a result of the substantial shift from the native binding mode and unfavorable local solvation environment. However, surprisingly, the underlying molecular pictures for the unfavorable binding of both ligands are quite distinctive: for PI(3,4)P2, it is due to a direct destabilization in the bound state, whereas for PI(3,4,5)P3, it is due to a relative stabilization in its free state. Our findings not only provide a theoretical basis for the ligand specificity, but also generate new insights into the allosteric modulation of ligand-gated ion channels.

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

Back to tab navigation

Supplementary files

Publication details

The article was received on 19 Mar 2018, accepted on 04 Sep 2018 and first published on 05 Sep 2018


Article type: Edge Article
DOI: 10.1039/C8SC01284A
Citation: Chem. Sci., 2018,9, 8352-8362
  • Open access: Creative Commons BY license
  •   Request permissions

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

    X. Meng, S. Kang and R. Zhou, Chem. Sci., 2018, 9, 8352
    DOI: 10.1039/C8SC01284A

    This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements