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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural insight into Ca~(2+) specificity in tetrameric cation channels
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Structural insight into Ca~(2+) specificity in tetrameric cation channels

机译：四聚阳离子通道中Ca〜（2+）特异性的结构洞察

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摘要

Apparent blockage of monovalent cation currents by the permeating blocker Ca~(2+) is a physiologically essential phenomenon relevant to cyclic nucleotide-gated (CNG) channels. The recently determined crystal structure of a bacterial homolog of CNG channel pores, the NaK channel, revealed a Ca~(2+) binding site at the extracellular entrance to the selectivity filter. This site is not formed by the side-chain carboxylate groups from the conserved acidic residue, Asp-66 in NaK, conventionally thought to directly chelate Ca~(2+) in CNG channels, but rather by the backbone carbonyl groups of residue Gly-67. Here we present a detailed structural analysis of the NaK channel with a focus on Ca~(2+) permeability and blockage. Our results confirm that the Asp-66 residue, although not involved in direct chelation of Ca~(2+), plays an essential role in external Ca~(2+) binding. Furthermore, we give evidence for the presence of a second Ca~(2+) binding site within the NaK selectivity filter where monovalent cations also bind, providing a structural basis for Ca~(2+) permeation through the NaK pore. Compared with other Ca~(2+)-binding proteins, both sites in NaK present a novel mode of Ca~(2+) chelation, using only backbone carbonyl oxygen atoms from residues in the selectivity filter. The external site is under indirect control by an acidic residue (Asp-66), making it Ca~(2+)-specific. These findings give us a glimpse of the possible underlying mechanisms allowing Ca~(2+) to act both as a permeating ion and blocker of CNG channels and raise the possibility of a similar chemistry governing Ca~(2+) chelation in Ca~(2+) channels.
机译：渗透阻滞剂Ca〜（2+）对单价阳离子电流的明显阻滞是与环核苷酸门控（CNG）通道有关的生理必需现象。最近确定的CNG通道孔的细菌同源物NaK通道的晶体结构揭示了在选择性过滤器的细胞外入口处有Ca〜（2+）结合位点。该位点不是由保守的NaK中酸性残基Asp-66的侧链羧酸盐基团形成，通常认为它直接螯合CNG通道中的Ca〜（2+），而是由残基Gly-的骨架羰基形成。 67。在这里，我们介绍了NaK通道的详细结构分析，重点是Ca〜（2+）的渗透性和阻塞。我们的结果证实，尽管Asp-66残基不参与Ca〜（2+）的直接螯合，但在外部Ca〜（2+）的结合中起着至关重要的作用。此外，我们提供了在NaK选择性过滤器中第二个Ca〜（2+）结合位点的存在的证据，其中一价阳离子也可以结合，从而为Ca〜（2+）穿过NaK孔的渗透提供了结构基础。与其他Ca〜（2+）结合蛋白相比，NaK中的两个位点都呈现出Ca〜（2+）螯合的新模式，仅使用选择性过滤器中残基的骨架羰基氧原子。外部位点受酸性残基（Asp-66）的间接控制，使其具有Ca〜（2+）特异性。这些发现使我们瞥见了可能的潜在机制，使Ca〜（2+）既充当CNG通道的渗透离子和阻断剂，又增加了类似化学作用控制Ca〜（2+）螯合的可能性。 2+）个频道。

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