NMDA receptor structures reveal subunit arrangement and pore architecture

摘要

N-methyl-D-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present X-ray crystal structures of the Xenopus laevis GluNl-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ton channel blockers and magnesium, and a ～twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.%谷氨酸盐是中枢神经系统中的主要激发性神经 传输物质，在促离子型谷氨酸受体和促代谢型 谷氨酸受体上发挥作用。促离子型谷氨酸受体 通过在谷氨酸盐结合时打开一个跨膜离子通道发挥功能。Eric Gouaux及同事报告了GluN1-GluN2B W-methyl-D-aspartate(NMDA)受体的 X-射线晶体结构。它是一个异四聚体复合物， 由一个与甘氨酸相结合的GluN1亚单元和一个 与谷氨酸盐相结合的GluN2亚单元组成。该受 体的激活会打开一个阳离子选择性的、钙可渗 透的通道，从而造成细胞膜的进一步去极化和 钙的流入。这一膜蛋白的结构是在与变构抑制 因子Ro25-6981、通道阻断因子MK-801和两 个部分激动剂(促效药)所形成的复合物中获得 的。这一膜蛋白的整体结构是蘑菇形的，其中 GluN1和GluN2B亚单元以1-2-1-2形式排列成 一个"二聚体的二聚体"（dimer-of-dimers)。