Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy
Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy
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DOI：
10.1038/ncomms6206
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发表时间：
2014-10-01
影响因子：
16.6
通讯作者：
Margeat, Emmanuel
中科院分区：
文献类型：
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作者：
Olofsson, Linnea;Felekyan, Suren;Margeat, Emmanuel
有效的细胞间通讯依赖于细胞表面受体的准确信号传导。了解其激活的分子基础需要表征活性和静息状态之间的动态平衡。在这里，我们监测，使用单分子福斯特共振能量转移，代谢型谷氨酸受体（mGluR），C类G-蛋白偶联受体的胞外配体结合结构域的重新取向的动力学。我们证明，大多数受体之间的休息和活跃的构象在亚毫秒的时间尺度上振荡。有趣的是，我们证明，激动剂功效的差异源于不同的能力，以改变构象平衡的完全活跃的状态，而不是从稳定的替代静态构象，这进一步突出了mGluRs的动态性质，并修改我们的理解受体活化和变构调节。
Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Forster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein-coupled receptor. We demonstrate that most receptors oscillate between a resting-and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation.