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

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

Author information

1
Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
2
1] [2].
3
U1006 INSERM, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13009 Marseille, France.
4
1] Forschungszentrum Jülich, Institute of Complex Systems, ICS-6: Structural Biochemistry, 52425 Jülich, Germany [2] Department of Physics, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
5
Departments of Anesthesiology, Physiology and Biophysics, and Biochemistry, Weill Cornell Medical College, 1300 York Ave, New York, New York 10065, USA.

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.

PMID:
24469021
PMCID:
PMC4086158
DOI:
10.1038/ncomms4106
[Indexed for MEDLINE]
Free PMC Article
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