Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
EMBO J. 2011 Mar 2;30(5):972-82. doi: 10.1038/emboj.2011.17. Epub 2011 Feb 11.
Glutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) sense the extracellular milieu via an extensive extracellular portion, comprised of two clamshell-shaped segments. The distal, N-terminal domain (NTD) has allosteric potential in NMDA-type iGluRs, which has not been ascribed to the analogous domain in AMPA receptors (AMPARs). In this study, we present new structural data uncovering dynamic properties of the GluA2 and GluA3 AMPAR NTDs. GluA3 features a zipped-open dimer interface with unconstrained lower clamshell lobes, reminiscent of metabotropic GluRs (mGluRs). The resulting labile interface supports interprotomer rotations, which can be transmitted to downstream receptor segments. Normal mode analysis reveals two dominant mechanisms of AMPAR NTD motion: intraprotomer clamshell motions and interprotomer counter-rotations, as well as accessible interconversion between AMPAR and mGluR conformations. In addition, we detect electron density for a potential ligand in the GluA2 interlobe cleft, which may trigger lobe motions. Together, these data support a dynamic role for the AMPAR NTDs, which widens the allosteric landscape of the receptor and could provide a novel target for ligand development.
谷氨酸门控离子通道（离子型谷氨酸受体，iGluRs）通过由两个蛤壳状片段组成的广泛的细胞外部分来感知细胞外环境。远侧、N 端结构域（NTD）在 NMDA 型 iGluRs 中具有变构潜能，但尚未归因于 AMPA 受体（AMPARs）中的类似结构域。在这项研究中，我们提供了新的结构数据，揭示了 GluA2 和 GluA3 AMPAR NTD 的动态特性。GluA3 具有拉链式打开的二聚体界面，其下蛤壳状结构域不受约束，类似于代谢型谷氨酸受体（mGluRs）。由此产生的不稳定界面支持蛋白间旋转，这种旋转可以传递到下游受体片段。正常模式分析揭示了 AMPAR NTD 运动的两种主要机制：蛋白内蛤壳运动和蛋白间反向旋转，以及 AMPAR 和 mGluR 构象之间的可转换性。此外，我们在 GluA2 间叶裂隙中检测到潜在配体的电子密度，这可能会引发叶运动。综上所述，这些数据支持 AMPAR NTDs 的动态作用，这拓宽了受体的变构景观，并可能为配体开发提供新的靶标。
