中国科学院上海有机化学研究所于杰小组宣布他们提出了天然NMDA受体的构象多样性及完全开放机制。相关论文于2026年2月11日发表在《自然》杂志上。

本研究通过免疫亲和纯化、单分子全内反射荧光显微镜和冷冻电子显微镜，从雌性C57BL/6小鼠全脑组织中鉴定并分离了10个不同的天然NMDAR片段。对GluN1-GluN2A （S1）、GluN1-GluN2A （S2）、GluN1-GluN2A （S3）、GluN1-GluN2B、GluN1-GluN2A-GluN2B （S1）、GluN1-GluN2A -GluN2B（S2）、GluN1-GluN2A - GluNX（S1）、GluN1-GluN2A -GluNX（S2）、GluN1-GluN2A -GluNX和GluN1-GluNX结构的分析表明，GluN2A是整个组合中最普遍的亚基。

此外，在GluN2A氨基末端结构域中观察到的大量构象灵活性可以解释其快速动力学和在门控中的主导作用。S-氯胺酮的动态运动也被捕获在通道前庭，以及天然GluN1 - GluN2B受体的GluN1和GluN2B亚基的孔扩张。后一种观察结果代表了以前未知的NMDAR的完全开放状态。他们从全脑收集的大量异质NMDAR结构揭示了以前未被认识到的构象多样性和通道扩张特性。

据介绍，N-甲基-d-天冬氨酸受体（NMDARs）是谷氨酸门控离子通道，介导整个大脑的兴奋性神经传递。作为专性异四聚体，它们的激活需要结合甘氨酸和谷氨酸。尽管最近的结构研究已经提供了对特定脑区内源性受体的见解，但大多数先前的工作都依赖于重组受体和工程结构，这限制了他们对整个大脑的天然NMDARs的理解。

附：英文原文

Title: Conformational diversity and fully opening mechanism of native NMDA receptor

Author: Xu, Ruisheng, Jiang, Qiqi, Xu, Hongwei, Zhang, Lu, Hu, Xiangzi, Lu, Zizhuo, Deng, Huaqin, Xiong, Haolin, Zhang, Sensen, Chen, Zhongwen, Ge, Yifan, Zhu, Zhengjiang, Zhang, Yaoyang, Chen, Yelin, Ge, Jingpeng, Yu, Jie

Issue&Volume: 2026-02-11

Abstract: N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission throughout the brain1. As obligate heterotetramers, their activation requires the binding of both glycine and glutamate2. Although recent structural studies have provided insights into endogenous receptors from select brain regions3, most previous work has relied on recombinant receptors and engineered constructs, which limits our understanding of native NMDARs across the whole brain. Here we identify and resolve ten distinct native NMDAR assemblies from the whole-brain tissue of female C57BL/6 mice using immunoaffinity purification, single-molecule total internal reflection fluorescence microscopy and cryo-electron microscopy. Analyses of the GluN1–GluN2A(S1), GluN1–GluN2A(S2), GluN1–GluN2A(S3), GluN1–GluN2B, GluN1–GluN2A–GluN2B(S1), GluN1–GluN2A–GluN2B(S2), GluN1–GluN2A–GluNX(S1), GluN1–GluN2A–GluNX(S2), GluN1–GluN2B–GluNX and GluN1–GluNX structures reveal that GluN2A is the most prevalent subunit across assemblies. Moreover, the substantial conformational flexibility observed in the GluN2A amino-terminal domain may explain its fast kinetics and dominant role in gating. Dynamic movements of S-ketamine were also captured at the channel vestibule, as was pore dilation in both the GluN1 and GluN2B subunits of a native GluN1–GluN2B receptor. The latter observation represents a previously unknown fully open state of NMDAR. Our large collection of heterogeneous NMDAR structures from whole brain reveals previously unrecognized properties of conformational diversity and channel dilation.

DOI: 10.1038/s41586-026-10139-w

Source: https://www.nature.com/articles/s41586-026-10139-w