Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel.
Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel.
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DOI：
10.1038/s41594-023-00955-3
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发表时间：
2023-04
影响因子：
16.8
通讯作者：
Scheuring, Simon
中科院分区：
文献类型：
--
作者：
Pan, Yangang;Pohjolainen, Emmi;Schmidpeter, Philipp A. M.;Vaiana, Andrea C.;Nimigean, Crina M.;Grubmueller, Helmut;Scheuring, Simon
环核苷酸门控离子通道在许多生理过程中是至关重要的，如视觉和心脏起搏。SthK是一种原核同源物，与超极化激活的、环核苷酸调节的和环核苷酸门控的通道具有高度的序列和结构相似性，特别是在环核苷酸结合结构域（CNBD）水平上。功能测量表明，环磷酸腺苷（cAMP）是一种通道激活剂，而环磷酸鸟苷（cGMP）几乎不导致孔开放。在这里，使用原子力显微镜单分子力光谱和力探针分子动力学模拟，我们解开定量和在原子水平上CNBDs如何区分环核苷酸。我们发现cAMP与SthK CNBD的结合略强于cGMP，并进入cGMP结合的CNBD无法达到的深度结合状态。我们认为，cAMP的深度结合是cAMP依赖性通道激活所必需的歧视性状态。
Cyclic nucleotide-gated ion channels are crucial in many physiological processes such as vision and pacemaking in the heart. SthK is a prokaryotic homolog with high sequence and structure similarities to hyperpolarization-activated and cyclic nucleotide-modulated and cyclic nucleotide-gated channels, especially at the level of the cyclic nucleotide binding domains (CNBDs). Functional measurements showed that cyclic adenosine monophosphate (cAMP) is a channel activator while cyclic guanosine monophosphate (cGMP) barely leads to pore opening. Here, using atomic force microscopy single-molecule force spectroscopy and force probe molecular dynamics simulations, we unravel quantitatively and at the atomic level how CNBDs discriminate between cyclic nucleotides. We find that cAMP binds to the SthK CNBD slightly stronger than cGMP and accesses a deep-bound state that a cGMP-bound CNBD cannot reach. We propose that the deep binding of cAMP is the discriminatory state that is essential for cAMP-dependent channel activation.
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真核环核苷酸门控通道的结构。
影响因子：
64.8
作者：
Li M;Zhou X;Wang S;Michailidis I;Gong Y;Su D;Li H;Li X;Yang J
通讯作者：
Yang J
DOI：
10.1073/pnas.070052697
发表时间：
2000-04-11
影响因子：
11.1
作者：
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影响因子：
3.4
作者：
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影响因子：
4.4
作者：
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影响因子：
17.1
作者：
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Fukuma, Takeshi