Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1

Nat Commun. 2014;5:3106. doi: 10.1038/ncomms4106.

Abstract

Cyclic nucleotide-modulated ion channels are important for signal transduction and pacemaking in eukaryotes. The molecular determinants of ligand gating in these channels are still unknown, mainly because of a lack of direct structural information. Here we report ligand-induced conformational changes in full-length MloK1, a cyclic nucleotide-modulated potassium channel from the bacterium Mesorhizobium loti, analysed by electron crystallography and atomic force microscopy. Upon cAMP binding, the cyclic nucleotide-binding domains move vertically towards the membrane, and directly contact the S1-S4 voltage sensor domains. This is accompanied by a significant shift and tilt of the voltage sensor domain helices. In both states, the inner pore-lining helices are in an 'open' conformation. We propose a mechanism in which ligand binding can favour pore opening via a direct interaction between the cyclic nucleotide-binding domains and voltage sensors. This offers a simple mechanistic hypothesis for the coupling between ligand gating and voltage sensing in eukaryotic HCN channels.

Publication types

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

MeSH terms

  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Cyclic AMP / metabolism
  • Ion Channel Gating
  • Ligands
  • Mesorhizobium / metabolism*
  • Microscopy, Atomic Force
  • Models, Molecular
  • Potassium Channels / chemistry*
  • Potassium Channels / metabolism

Substances

  • Bacterial Proteins
  • Ligands
  • Potassium Channels
  • Cyclic AMP

Associated data

  • PDB/4CHV
  • PDB/4CHW