Crystal structure of the ATP-gated P2X4 ion channel in the closed state

P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X4 receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit–subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in β-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the ‘gate’ is defined by an ∼8 Å slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening. P2X receptors are ATP-gated non-selective cation channels involved in nociception and inflammatory responses, whose structures were unknown. Kawate et al. now present the crystal structure of the zebrafish P2X4 receptor in a closed state. The trimeric structure reveals some of the molecular underpinnings of ligand-binding, cation entry and channel gating. A related paper presents the structure of chicken acid-sensing ion channel 1 (ASIC1) in a desensitized state. Like P2X receptors, ASICs are trimeric, but they belong to an entirely different family of ion channels. The structure determination of ASIC1 shows how ion permeation and desensitization may occur, and comparison of ASIC and P2X structures suggests that these functionally distinct channels employ similar mechanistic principles. P2X receptors are ATP-gated cation channels that are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. The crystal structure of the zebrafish P2X4 channel is now solved in its closed state, revealing some of the molecular underpinnings of ligand-binding, cation entry and channel gating.