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摘要 : TRP (transient receptor potential)通道所有真核生物都表达,充当一系列不同物理和化学刺激的传感器。这篇论文报告了人类全长度TRPA1 (有害化学物质如“山葵”的一个感觉受体)的高分辨率低温电子显微镜结构。

 TRP (transient receptor potential)通道所有真核生物都表达,充当一系列不同物理和化学刺激的传感器。这篇论文报告了人类全长度TRPA1 (有害化学物质如“山葵”的一个感觉受体)的高分辨率低温电子显微镜结构。这一膜蛋白的整体结构与以前发表的TRPV1的结构显著不同,因为TRPA1有很多锚蛋白重复域、一个位于该通道中心的四聚卷曲螺旋(它似乎充当“肌醇六磷酸”的一个结合点)和一个具有两个空隙螺旋的外空隙域。TRPA1与持续性疼痛、呼吸病和慢性瘙痒相关,所以TRPA1拮抗剂有望用作镇痛剂。


Structure of the TRPA1 ion channel suggests regulatory mechanisms


The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to ~4 Å resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.

对应Nature杂志: 2015年04月23日Nature杂志精选

来源: Nature 浏览次数:2


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