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Title: Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels
Authors: Kondapuram, Mahesh
Frieg, Benedikt
Yüksel, Sezin
Schwabe, Tina
Sattler, Christian
Lelle, Marco
Schweinitz, Andrea
Schmauder, Ralf
Benndorf, Klaus
Gohlke, Holger
Kusch, Jana
Keywords: HCN channel
molecular dynamics simulations
subunit interaction
patch-clamp technique
confocal patch-clamp fluorometry
Issue Date: 5-Aug-2021
Publisher: N/A
Abstract: Hyperpolarization-activated and cyclic nucleotide (HCN) modulated channels are tetrameric cation channels. In each of the four subunits, the intracellular cyclic nucleotide-binding domain (CNBD) is coupled to the transmembrane domain via a helical structure, the C-linker. High-resolution channel structures suggest that the C-linker enables functionally relevant interactions with the opposite subunit, which might be critical for coupling the conformational changes in the CNBD to the channel pore. We combined mutagenesis, patch-clamp technique, confocal patch-clamp fluorometry, and molecular dynamics simulations to show that residue K464 of the C-linker is essential for stabilizing the closed state of the mHCN2 channel by forming interactions with the opposite subunit. MD simulations revealed that both cAMP and K464E induce a rotation of the intracellular domain relative to the channel pore, weakening the autoinhibitory effect of the unoccupied CL-CNBD region. The adopted poses are in excellent agreement with structural results.
Appears in Collections:Computational Pharmaceutical Chemistry and Molecular Informatics Group

Files in This Item:
File Description SizeFormat 
DATA_SOURCE_MDsimulation_Modelling.xlsxMD simulations data34.15 kBMicrosoft Excel XMLView/Open
Data Source Electrophysiology.xlsxElectrophysiological data35.21 kBMicrosoft Excel XMLView/Open
Data Source Patch-Clamp-Fluorometry.xlsxFluorescence data9.29 kBMicrosoft Excel XMLView/Open
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