Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, National Institute of Child Health and Human Development, Department of Health and Human Services, National Institutes of Health, Bethesda, MD 20892, USA.
Structure. 2013 Oct 8;21(10):1788-99. doi: 10.1016/j.str.2013.07.011. Epub 2013 Aug 22.
The NMDA receptor family of glutamate receptor ion channels is 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 suggest 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.
NMDA 受体家族的谷氨酸受体离子通道由 GluN1、GluN2 和 GluN3 亚基的必需异源二聚体组成。GluN1 和 GluN3 结合甘氨酸，而 GluN2 结合谷氨酸。GluN1 和 GluN3A 配体结合域 (LBD) 的晶体结构在其apo 状态下出人意料地分别呈现开放和闭合裂隙构象，水分子填充结合口袋。GluN1、GluN2A 和 GluN3A LBD 的计算构象自由能景观表明，apo 状态的 LBD 采样闭合裂隙构象，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，谷氨酸通过诱导契合机制结合。主成分分析揭示了丰富的铰链弯曲、摇摆、扭曲和扫荡运动谱，这些运动在 GluN1、GluN2A、GluN3A 和 GluA2 LBD 之间是不同的。这种变化突出了谷氨酸受体离子通道信号转导的结构复杂性。
