X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor

摘要

中枢神经系统中的大多数兴奋型神经传输(允rn许神经元彼此沟通的事件)是由离子型谷氦酸rn盐受体调控的，这些受体通过打开结合谷氨rn酸盐上的一个跨膜离子通道发挥作用。过去rn人们对它们的总体结构知之甚少，但现在Erucrn Gouaux及其同事报告了结合到一个竞争性拮rn抗剂上的对AMPA敏感的亚型“大鼠GluA2受rn体”的×-射线晶体结构。该受体(如封面图片rn所示)具有一个出乎意料的对称性和亚单元排rn列：总体上为双重对称，细胞外区域按局部rn二聚体对的形式来组织。离子通道区域表现rn出四重对称。这种结构(是根据来自定点诱变rn实验的数据获得的)表明，对NMDA敏感的受体rnGtuN1和GluN2A在总体结构上与GluA2相似。rn从这些结构可以推断出非竞争性拮抗剂和孔阻rn断分子对离子通道的激发、脱敏和抑制机制。%Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-D-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.