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000890666 005__ 20210222133906.0
000890666 0247_ $$2doi$$a10.1101/2020.09.21.305797
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000890666 1001_ $$aKondapuram, Mahesh$$b0
000890666 245__ $$aFunctional and structural characterization of interactions between opposite subunits in HCN pacemaker channels
000890666 260__ $$aCold Spring Harbor$$bCold Spring Harbor Laboratory, NY$$c2020
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000890666 520__ $$aHyperpolarization-activated and cyclic nucleotide (HCN) modulated channels are tetrameric cation channels. In each of the four subunits, the intracellular cyclic nucleotide-binding domain (CNBD) is coupled to the transmembrane domain via a helical structure, the C-linker. High-resolution channel structures suggest that the C-linker enables functionally relevant interactions with the opposite subunit, which might be critical for coupling the conformational changes in the CNBD to the channel pore. We combined mutagenesis, patch-clamp technique, confocal patch-clamp fluorometry, and molecular dynamics simulations to show that residue K464 of the C-linker is essential for stabilizing the closed state of the mHCN2 channel by forming interactions with the opposite subunit. MD simulations revealed that both cAMP and K464E induce a rotation of the intracellular domain relative to the channel pore, weakening the autoinhibitory effect of the unoccupied CL-CNBD region. The adopted poses are in excellent agreement with structural results.
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000890666 7001_ $$0P:(DE-Juel1)172887$$aFrieg, Benedikt$$b1
000890666 7001_ $$aYüksel, Sezin$$b2
000890666 7001_ $$aSchwabe, Tina$$b3
000890666 7001_ $$aSattler, Christian$$b4
000890666 7001_ $$aLelle, Marco$$b5
000890666 7001_ $$aSchweinitz, Andrea$$b6
000890666 7001_ $$aSchmauder, Ralf$$b7
000890666 7001_ $$00000-0002-0707-4083$$aBenndorf, Klaus$$b8
000890666 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b9
000890666 7001_ $$00000-0001-7206-8133$$aKusch, Jana$$b10
000890666 773__ $$0PERI:(DE-600)2766415-6$$a10.1101/2020.09.21.305797$$tbioRxiv beta$$y2020
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