Lu Xuhang, Li Dongmei, Wang Yaojie, Zhang Gaohua, Wen Tianlei, Lu Yue, Jia Nan, Wang Xuedi, Chang Shenghai, Zhang Xing, Lin Jianping, Chen Yu-Hang, Yang Xue, Shen Yuequan
State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300350, China.
College of Pharmacy, Nankai University, Tianjin, 300350, China.
Nat Commun. 2025 Jan 7;16(1):442. doi: 10.1038/s41467-024-55807-5.
The zinc-activated channel (ZAC) is an atypical mammalian cys-loop receptor (CLR) that is activated by zinc ions and protons, allowing cations to pass through. The molecular mechanism that ligands use to activate ZAC remains elusive. Here, we present three cryo-electron microscopy reconstructions of human ZAC (hZAC) under different conditions. These three hZAC structures display highly similar conformations to one another, forming symmetrical homo-pentamers with a central ion-conduction pore. The hZAC protomer comprises an extracellular domain (ECD) and a transmembrane domain (TMD), sharing more structural similarity with anion-permeable CLRs, such as glycine receptors and type A γ-aminobutyric acid receptors. Notably, hZAC possesses a distinctive C-tail that establishes a disulfide bond with the loop M2-M3 in the TMD and occupies what is typically the canonical neurotransmitter orthosteric site in other mammalian CLRs. Moreover, the tip of the cys-loop creates an unprecedented orthosteric site in hZAC. The binding of Zn triggers a conformational shift in the cys-loop, which presumably prompts the loop M2-M3 to move and open the channel gate. This study sheds light on the assembly of the channel, its structural features, and the process of signal transduction in hZAC.
锌激活通道（ZAC）是一种非典型的哺乳动物半胱氨酸环受体（CLR），可被锌离子和质子激活，允许阳离子通过。配体用于激活ZAC的分子机制仍然不清楚。在这里，我们展示了在不同条件下人类ZAC（hZAC）的三种冷冻电子显微镜重建结构。这三种hZAC结构彼此呈现高度相似的构象，形成具有中央离子传导孔的对称同五聚体。hZAC原体包括一个细胞外结构域（ECD）和一个跨膜结构域（TMD），与阴离子通透的CLR（如甘氨酸受体和A型γ-氨基丁酸受体）具有更多的结构相似性。值得注意的是，hZAC拥有一个独特的C末端，该末端与TMD中的M2-M3环形成二硫键，并占据了其他哺乳动物CLR中通常为典型神经递质正构位点的位置。此外，半胱氨酸环的末端在hZAC中创造了一个前所未有的正构位点。锌的结合触发了半胱氨酸环的构象变化，这可能促使M2-M3环移动并打开通道门。这项研究揭示了hZAC通道的组装、其结构特征以及信号转导过程。
