Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.
Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.
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DOI：
10.1038/nature10180
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发表时间：
2011-06-15
期刊：
影响因子：
64.8
通讯作者：
Furukawa H
中科院分区：
文献类型：
--
作者：
Karakas E;Simorowski N;Furukawa H
自从人们意外地发现降压药ifenprodil通过对N-甲基-D-天冬氨酸(NMDA)受体的作用而具有神经保护活性以来，人们做出了巨大的努力来了解其作用机制，并在此基础上开发出改进的治疗化合物。NMDA受体介导的神经传递对大脑的基本发育和功能是必不可少的。这些受体形成异构体离子通道，并在甘氨酸和谷氨酸分别与GluN1和GluN2亚基同时结合时激活。NMDA受体的一个功能标志是其离子通道活性受小分子以亚型特异性方式与氨基末端结构域(ATD)结合的变构调节。异丙苯地尔和相关的苯乙醇胺类化合物可以特异性地抑制GluN1/GluN2B NMDA受体，由于它们可能用于治疗各种神经疾病和疾病，包括抑郁症、阿尔茨海默病和帕金森病，因此受到了广泛的研究。尽管人们热情高涨，但由于缺乏结构信息，苯乙醇胺的识别和ATD介导的变构抑制的潜在机制仍然有限。在这里，我们报告了GluN1和GluN2B ATD形成异二聚体，苯乙醇胺结合在GluN1-GluN2B亚单位界面上，而不是在GluN2B裂隙内。GluN1b/GluN2B ATD异源二聚体的晶体结构显示了与同源二聚体非NMDA受体不同的亚基排列模式，揭示了苯乙醇胺结合的分子决定因素。通过设计亚基间二硫键来限制GluN2B ATD双叶结构中的结构域运动，显着降低了对异丙苯地尔的敏感性，这表明GluN2B ATD中的构象自由是依芬普地尔介导的NMDA受体变构抑制所必需的。
Since it was unexpectedly discovered that the anti-hypertensive agent, ifenprodil, has neuroprotective activity through effects to N-methyl-D-aspartate (NMDA) receptors, enormous efforts have been made to understand the mechanism of action and to develop improved therapeutic compounds based on this knowledge. Neurotransmission mediated by NMDA receptors is essential for basic brain development and function. These receptors form heteromeric ion channels and become activated upon concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion channel activity is allosterically regulated by binding of small compounds to the amino terminal domain (ATD) in a subtype specific manner. Ifenprodil and related phenylethanolamine compounds, which specifically inhibit GluN1/GluN2B NMDA receptors, have been intensely studied for their potential use in treatment of various neurological disorders and diseases including depression, Alzheimer’s disease and Parkinson’s disease. Despite great enthusiasm, mechanisms underlying recognition of phenylethanolamines and the ATD-mediated allosteric inhibition remain limited due to lack of structural information. Here we report that the GluN1 and GluN2B ATDs form heterodimer and that phenylethanolamine binds at the GluN1-GluN2B subunit interface rather than within the GluN2B cleft. The crystal structure of the GluN1b/GluN2B ATD heterodimer shows a highly distinct pattern of subunit arrangement that is different from those observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structures of the GluN2B ATD by engineering an inter-subunit disulfide bond dramatically decreases ifenprodil-sensitivity indicating that conformational freedom in the GluN2B ATD is essential for ifenprodil-mediated allosteric inhibition in NMDA receptors.