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@ARTICLE{Kondapuram:907779,
author = {Kondapuram, Mahesh and Frieg, Benedikt and Yüksel, Sezin
and Schwabe, Tina and Sattler, Christian and Lelle, Marco
and Schweinitz, Andrea and Schmauder, Ralf and Benndorf,
Klaus and Gohlke, Holger and Kusch, Jana},
title = {{F}unctional and structural characterization of
interactions between opposite subunits in {HCN} pacemaker
channels},
journal = {Communications biology},
volume = {5},
number = {1},
issn = {2399-3642},
address = {London},
publisher = {Springer Nature},
reportid = {FZJ-2022-02208},
pages = {430},
year = {2022},
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 (MD)
simulations to show that residue K464 of the C-linker is
relevant for stabilizing the closed state of the mHCN2
channel by forming interactions with the opposite subunit.
MD simulations revealed that in the K464E channel, a
rotation of the intracellular domain relative to the channel
pore is induced, which is similar to the cAMP-induced
rotation, weakening the autoinhibitory effect of the
unoccupied CL-CNBD region. We suggest that this CL-CNBD
rotation is considerably involved in activation-induced
affinity increase but only indirectly involved in gate
modulation. The adopted poses shown herein are in excellent
agreement with previous structural results.},
cin = {IBG-4 / JSC / NIC / IBI-7},
ddc = {570},
cid = {I:(DE-Juel1)IBG-4-20200403 / I:(DE-Juel1)JSC-20090406 /
I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)IBI-7-20200312},
pnm = {5111 - Domain-Specific Simulation $\&$ Data Life Cycle Labs
(SDLs) and Research Groups (POF4-511) / 2171 - Biological
and environmental resources for sustainable use (POF4-217) /
Forschergruppe Gohlke $(hkf7_20200501)$ / 5241 - Molecular
Information Processing in Cellular Systems (POF4-524)},
pid = {G:(DE-HGF)POF4-5111 / G:(DE-HGF)POF4-2171 /
$G:(DE-Juel1)hkf7_20200501$ / G:(DE-HGF)POF4-5241},
typ = {PUB:(DE-HGF)16},
pubmed = {35534535},
UT = {WOS:000792648600004},
doi = {10.1038/s42003-022-03360-6},
url = {https://juser.fz-juelich.de/record/907779},
}