美国俄勒冈健康与科学大学Steven E. Mansoor团队在研究中取得进展。他们利用全长的P2X7受体结构揭示了棕榈酰化修饰如何防止通道脱敏。2019年10月3日，该论文在线发表于国际学术期刊《细胞》。
研究人员报道了在apo和ATP结合状态的全长大鼠P2X7受体的冷冻电镜结构。这些结构揭示了C-cys锚是一种细胞质元件如何通过将带有孔的螺旋固定在具有棕榈酰基的膜上来防止脱敏。它们显示出具有独特折叠的第二种胞质元件，即胞质压舱物，其出乎意料地包含锌离子复合物和鸟苷核苷酸结合位点。这一结构为P2X受体胞质域的结构和功能提供了初步见解。
研究人员介绍，P2X受体是三聚体非选择性阳离子通道，由细胞外ATP所激活。P2X7受体亚型是一种药理靶标，因为它参与了凋亡、炎症和肿瘤的进展途径。它是结构和功能上最独特的P2X亚型，包含一个独特的胞质结构域，其对受体启动细胞凋亡而不发生脱敏作用至关重要。但是，缺乏有关胞质域的结构信息阻碍了对这些过程的分子机制的理解。
附：英文原文
Title: Full-Length P2X7 Structures Reveal How Palmitoylation Prevents Channel Desensitization
Author: Alanna E. McCarthy, Craig Yoshioka, Steven E. Mansoor
Issue&Volume: 3 October 2019
Abstract:P2X receptors are trimeric, non-selective cation channels activated by extracellular ATP. The P2X7 receptor subtype is a pharmacological target because of involvement in apoptotic, inflammatory, and tumor progression pathways. It is the most structurally and functionally distinct P2X subtype, containing a unique cytoplasmic domain critical for the receptor to initiate apoptosis and not undergo desensitization. However, lack of structural information about the cytoplasmic domain has hindered understanding of the molecular mechanisms underlying these processes. We report cryoelectron microscopy structures of full-length rat P2X7 receptor in apo and ATP-bound states. These structures reveal how one cytoplasmic element, the C-cys anchor, prevents desensitization by anchoring the pore-lining helix to the membrane with palmitoyl groups. They show a second cytoplasmic element with a unique fold, the cytoplasmic ballast, which unexpectedly contains a zinc ion complex and a guanosine nucleotide binding site. Our structures provide first insights into the architecture and function of a P2X receptor cytoplasmic domain.
DOI: 10.1016/j.cell.2019.09.017
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31068-2