TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) -modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1–S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.

中文翻译：

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钙激活的非选择性阳离子通道 TRPM4 的结构

TRPM4 是一种钙激活、磷脂酰肌醇-4,5-二磷酸 (PtdIns(4,5)P2) 调节的非选择性阳离子通道，属于与褪黑素相关的瞬时受体电位 (TRPM) 通道家族。在这里，我们展示了有和没有 ATP 的小鼠 TRPM4 通道的电子冷冻显微镜结构。TRPM4 由多个跨膜和胞质结构域组成，它们组装成一个三层结构。N端核苷酸结合结构域和C端卷曲螺旋参与通道的四聚体组装；ATP 在核苷酸结合结构域结合并抑制通道活性。TRPM4 有一个特别宽的过滤器，但只能透过一价阳离子；滤渣 Gln973 对定义单价选择性至关重要。S1-S4 域和 S6 后 TRP 域形成中央门控装置，可能容纳 Ca2+- 和 PtdIns(4,5)P2 结合位点。这些结构为阐明 TRPM4 的复杂门控机制和揭示 TRPM 家族的分子结构提供了一个重要的起点。