The mammalian cysteine-loop receptor (CLR) family, comprising ligand-gated cation and anion channels, is highly expressed in the mammalian nervous system and has long been a critical target for neuropsychiatric drugs. In addition to clinically approved medications, some CLRs are also targets for recreational and illicit drugs, mediating the neurotoxic effects of various synthetic, plant-derived, and animal-derived compounds. Human CLRs include γ-aminobutyric acid (GABA) and glycine-gated anion channels (GABA_AR, GlyR), as well as acetylcholine (nACh), serotonin (5-HT) isoform 3, and zinc-activated cation channels (nAChR, 5-HT₃R, ZAC). However, the limited structural information available for ZAC over the years has hindered the investigation of its channel function and the development of drugs targeting related diseases.

On January 7, 2025, Yuequan Shen, Xue Yang, Yu-hang Chen, and Jianping Lin published an article titled "Structural insights into the activation mechanism of the human zinc-activated channel" in Nature Communications. In this study, cryo-EM was employed to resolve the structure of full-length human ZAC (hZAC) under three different conditions: ligand-free (hZAC-apo), acidic pH 4.0 (hZAC-acid), and Zn²⁺-bound (hZAC-Zn), with overall resolutions of 2.8 Å, 2.8 Å, and 2.9 Å, respectively. The elucidation of these structures provides valuable insights into the ligand-binding process and signal transduction mechanism of ZAC.

The structure revealed that hZAC exhibits homo-pentameric assembly across different states, with the cationic pore located at the center of the channel. hZAC is notably distinct from the other four receptors in the same family (nAChR, 5-HT₃R, GABA_AR, GlyR) and demonstrates several novel structural and functional characteristics: (1) it possesses a unique C-terminal tail (C-tail), which occupies the classical orthosteric binding site for neurotransmitter small molecules (loop C) in other mammalian CLRs and forms disulfide bonds with the M2-M3 loop in the transmembrane helical domain (TMD); (2) hZAC has a biological function of self-inhibition mediated by its C-tail; (3) hZAC is the first mammalian CLR found to use the Cys-loop as an orthosteric ligand-binding site; (4) no classical activation conformational pathways observed in other CLR family members were identified. Instead, the binding of Zn²⁺ directly triggers a conformational transition in the Cys-loop, and hydrophobic interactions between residues F164 and L283 induce movement in the M2-M3 loop, opening the channel gate.

This study provides insights into the assembly, structural characteristics, and signal transduction processes of hZAC. Future research is expected to uncover the mechanisms underlying hZAC-related pathogenesis and facilitate the development of targeted drugs.