Structural basis of kainate subtype glutamate receptor desensitization.
Structural basis of kainate subtype glutamate receptor desensitization.
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DOI：
10.1038/nature19352
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发表时间：
2016-09-22
期刊：
影响因子：
64.8
通讯作者：
Subramaniam, Sriram
中科院分区：
文献类型：
--
作者：
Meyerson, Joel R.;Chittori, Sagar;Merk, Alan;Rao, Prashant;Han, Tae Hee;Serpe, Mihaela;Mayer, Mark L.;Subramaniam, Sriram
谷氨酸受体是配体门控四聚体离子通道，介导中枢神经系统中的突触传递。它们在脊椎动物的认知中发挥着重要作用，它们的功能障碍是多种疾病的基础。在 AMPA 和红藻氨酸亚型谷氨酸受体的静息和脱敏状态下，离子通道都是关闭的，而与通道物理耦合的配体结合域则采用显着不同的构象。如果没有脱敏状态的原子模型，就不可能解决受体门控的核心问题：静息状态和脱敏受体状态如何显示闭合离子通道，即使它们在配体结合域的四级结构上存在重大差异。通过以 3.8 Å 分辨率测定红藻氨酸受体 GluK2 亚型脱敏状态的冷冻电镜结构，我们发现脱敏的特征是在受体的配体结合域层中建立环状结构。这种“脱敏环”的形成是由相邻亚基之间的交错螺旋接触介导的，这导致配体结合域的伪四重对称排列，说明了作为门控机制核心的对称性的微妙变化。脱敏环的破坏可能是使受体恢复到静止状态的关键开关，从而完成门控循环。
Glutamate receptors are ligand gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases. In both the resting and desensitized states of AMPA and kainate subtype glutamate receptors the ion channels are closed while the ligand binding domain, which is physically coupled to the channel, adopts dramatically different conformations. Without an atomic model for the desensitized state, it is not possible to address a central question in receptor gating: how the resting and desensitized receptor states both display closed ion channels, even though they have major differences in quaternary structure of the ligand binding domain. By determining the cryo-EM structure of the kainate receptor GluK2 subtype in its desensitized state at 3.8 Å resolution, we show that desensitization is characterized by establishment of a ring-like structure in the ligand binding domain layer of the receptor. Formation of this “desensitization ring” is mediated by staggered helix contacts between adjacent subunits, which leads to a pseudo four-fold symmetric arrangement of the ligand binding domains, illustrating subtle changes in symmetry that are at the heart of the gating mechanism. Disruption of the desensitization ring is likely the key switch that enables restoration of the receptor to its resting state, thereby completing the gating cycle.
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AMPA受体GLUA2在休息，预开口和脱敏状态中的结构和动力学。
影响因子：
64.5
作者：
Dürr KL;Chen L;Stein RA;De Zorzi R;Folea IM;Walz T;Mchaourab HS;Gouaux E
通讯作者：
Gouaux E
电子计数和束诱导运动校正可实现近原子分辨率的单粒子冷冻电镜。
影响因子：
48
作者：
Li, Xueming;Mooney, Paul;Zheng, Shawn;Booth, Christopher R.;Braunfeld, Michael B.;Gubbens, Sander;Agard, David A.;Cheng, Yifan
通讯作者：
Cheng, Yifan
影响因子：
16.2
作者：
Dawe GB;Musgaard M;Aurousseau MRP;Nayeem N;Green T;Biggin PC;Bowie D
通讯作者：
Bowie D
DOI：
10.1126/science.aad3873
发表时间：
2016-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Herguedas B;García-Nafría J;Cais O;Fernández-Leiro R;Krieger J;Ho H;Greger IH
通讯作者：
Greger IH
DOI：
10.1016/j.str.2015.07.002
发表时间：
2015-09-01
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Dutta A;Krieger J;Lee JY;Garcia-Nafria J;Greger IH;Bahar I
通讯作者：
Bahar I