Mansoor Steven E, Lü Wei, Oosterheert Wout, Shekhar Mrinal, Tajkhorshid Emad, Gouaux Eric
Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
Knight Cardiovascular Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
Nature. 2016 Oct 6;538(7623):66-71. doi: 10.1038/nature19367. Epub 2016 Sep 14.
P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states. The open state structure harbours an intracellular motif we term the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents.
P2X受体是三聚体、非选择性阳离子通道，可被ATP激活，在心血管、神经和免疫系统中发挥重要作用。尽管它们在人体生理学中具有核心功能，并且是治疗药物的潜在靶点，但目前尚无人类P2X受体的结构。这些受体的脱敏和离子渗透机制、拮抗原理以及形成孔道的跨膜结构域的完整结构仍不清楚。在此，我们报告了人类P2X受体在无配体/静息、激动剂结合/开放孔道、激动剂结合/封闭孔道/脱敏和拮抗剂结合/封闭状态下的X射线晶体结构。开放状态结构包含一个我们称为“细胞质帽”的细胞内基序，它稳定离子通道孔的开放状态，并为水和离子流出形成侧向的、内衬磷脂的细胞质窗孔。竞争性拮抗剂TNP-ATP和A-317491稳定无配体/静息状态，并揭示了负责竞争性抑制的相互作用。这些结构阐明了P2X受体门控的构象重排，并为开发新的药物提供了基础。
