伊芬普地尔
NMDA受体
致电离效应
化学
变构调节
受体
谷氨酸受体
生物物理学
离子通道
AMPA受体
长期抑郁
离子型谷氨酸受体
蛋白质亚单位
配体门控离子通道
神经科学
生物化学
生物
基因
作者
N. Tajima,Erkan Karakaş,Timothy Grant,Noriko Simorowski,Ruben Diaz-Avalos,Nikolaus Grigorieff,Hiro Furukawa
出处
期刊:Nature
[Springer Nature]
日期:2016-05-02
卷期号:534 (7605): 63-68
被引量:192
摘要
The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1–GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1–GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel. X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology were used to study the conformational changes that take place during the activation and inhibition of a mammalian GluN1b–GluN2B N-methyl-d-aspartate receptor. NMDA (N-methyl-D-aspartate) receptors are ionotropic glutamate receptors that are involved in brain development and function, including learning and memory formation, and dysfunctional NMDA receptors are associated with various neurological diseases and disorders. These membrane proteins are heterotetramers, comprising two copies each of the GluN1 and GluN2 subunits, which bind glycine and L-glutamate, respectively. Hiro Furukawa and colleagues use X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to study the conformational changes that take place during the activation and inhibition of rat NMDA receptors. In the absence of the allosteric inhibitor ifenprodil, the bi-lobed structure of GluN2 amino-terminal domain adopts an open conformation accompanied by rearrangement of the GluN1–GluN2 amino-terminal domain heterodimeric interface, altering subunit orientation in the ligand-binding and amino-terminal domains to form an active receptor conformation that gates the ion channel.
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