Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM, Paris, France.
Unité INSERM U1195, Hôpital de Bicêtre, Université Paris-Saclay, Paris, Le Kremlin-Bicêtre, France.
Nat Commun. 2021 Aug 5;12(1):4709. doi: 10.1038/s41467-021-25058-9.
Allostery represents a fundamental mechanism of biological regulation that involves long-range communication between distant protein sites. It also provides a powerful framework for novel therapeutics. NMDA receptors (NMDARs), glutamate-gated ionotropic receptors that play central roles in synapse maturation and plasticity, are prototypical allosteric machines harboring large extracellular N-terminal domains (NTDs) that provide allosteric control of key receptor properties with impact on cognition and behavior. It is commonly thought that GluN2A and GluN2B receptors, the two predominant NMDAR subtypes in the adult brain, share similar allosteric transitions. Here, combining functional and structural interrogation, we reveal that GluN2A and GluN2B receptors utilize different long-distance allosteric mechanisms involving distinct subunit-subunit interfaces and molecular rearrangements. NMDARs have thus evolved multiple levels of subunit-specific allosteric control over their transmembrane ion channel pore. Our results uncover an unsuspected diversity in NMDAR molecular mechanisms with important implications for receptor physiology and precision drug development.
变构作用代表了一种基本的生物学调节机制，涉及到蛋白质远部位点之间的长程通讯。它也为新型治疗方法提供了一个强大的框架。N-甲基-D-天冬氨酸受体（NMDARs）是谷氨酸门控离子型受体，在突触成熟和可塑性中发挥核心作用，是典型的变构机器，具有大的细胞外 N 端结构域（NTD），对关键受体特性进行变构控制，从而影响认知和行为。通常认为，在成年脑中占主导地位的两种 NMDAR 亚型 GluN2A 和 GluN2B 受体具有相似的变构转变。在这里，我们结合功能和结构研究，揭示了 GluN2A 和 GluN2B 受体利用不同的长程变构机制，涉及不同的亚基-亚基界面和分子重排。NMDAR 因此进化出了对其跨膜离子通道孔的多层次亚基特异性变构控制。我们的研究结果揭示了 NMDAR 分子机制的一种意想不到的多样性，这对受体生理学和精确药物开发具有重要意义。
