4KL1

HCN4 CNBD in complex with cGMP

4KL1 の概要

• エントリーDOI: 10.2210/pdb4kl1/pdb
• 関連するPDBエントリー: 1Q3E 3OTF 3U0Z 3U10 3U11 4HBN
• 分子名称: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, CYCLIC GUANOSINE MONOPHOSPHATE, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: cnbd, camp, cgmp, c-di-gmp, c-di-amp, ion channel, hcn, potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel, camp binding, cgmp binding, protein transport
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane; Multi-pass membrane protein: Q9Y3Q4
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 96744.53

構造登録者

Lolicato, M.,Arrigoni, C.,Zucca, S.,Nardini, M.,Bucchi, A.,Schroeder, I.,Simmons, K.,Bolognesi, M.,DiFrancesco, D.,Schwede, F.,Fishwick, C.W.G.,Johnson, A.P.K.,Thiel, G.,Moroni, A. (登録日: 2013-05-07, 公開日: 2014-04-30, 最終更新日: 2024-11-06)

主引用文献

Lolicato, M.,Bucchi, A.,Arrigoni, C.,Zucca, S.,Nardini, M.,Schroeder, I.,Simmons, K.,Aquila, M.,DiFrancesco, D.,Bolognesi, M.,Schwede, F.,Kashin, D.,Fishwick, C.W.,Johnson, A.P.,Thiel, G.,Moroni, A.
Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.
Nat.Chem.Biol., 10:457-462, 2014

PubMed Abstract: cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder β-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system.

PubMed: 24776929
DOI: 10.1038/nchembio.1521

実験手法

X-RAY DIFFRACTION (2.7 Å)