Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics.
Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics.
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DOI：
10.1016/j.str.2013.07.011
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发表时间：
2013-10-08
期刊：
影响因子：
5.7
通讯作者：
Lau, Albert Y.
中科院分区：
文献类型：
--
作者：
Yao, Yongneng;Belcher, John;Berger, Anthony J.;Mayer, Mark L.;Lau, Albert Y.
谷氨酸受体离子通道的NMDA受体家族由GluN1、GluN2和GluN3亚基的专性异聚体组装形成。GluN1和GluN3结合甘氨酸，而GluN2结合谷氨酸。GluN1和GluN3A配体结合域（LBD）在其载脂蛋白状态的晶体结构意外地揭示了开放和封闭的裂缝构象，分别与水分子填充的结合口袋。计算构象自由能景观GluN1，GluN2A，和GluN3A LBD显示，载脂蛋白状态LBD样品封闭裂缝构象，这表明它们的激动剂通过构象选择机制结合。相比之下，AMPA受体GluA2 LBD的自由能景观表明谷氨酸通过诱导适应机制结合。主成分分析揭示了一个丰富的频谱铰链弯曲，摇摆，扭转，和清扫运动是不同的GluN1，GluN2A，GluN3A，和GluA2 LBD。这种变化凸显了谷氨酸受体离子通道信号传导的结构复杂性。
The NMDA receptor family of glutamate receptor ion channels are formed by obligate heteromeric assemblies of GluN1, GluN2 and GluN3 subunits. GluN1 and GluN3 bind glycine, whereas GluN2 binds glutamate. Crystal structures of the GluN1 and GluN3A ligand-binding domains (LBDs) in their apo states unexpectedly reveal open and closed cleft conformations, respectively, with water molecules filling the binding pockets. Computed conformational free energy landscapes for GluN1, GluN2A, and GluN3A LBDs reveal that the apo state LBDs sample closed cleft conformations, suggesting that their agonists bind via a conformational selection mechanism. By contrast, free energy landscapes for the AMPA receptor GluA2 LBD suggests binding of glutamate via an induced fit mechanism. Principal component analysis reveals a rich spectrum of hinge bending, rocking, twisting, and sweeping motions that are different for the GluN1, GluN2A, GluN3A, and GluA2 LBDs. This variation highlights the structural complexity of signaling by glutamate receptor ion channels.
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影响因子：
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