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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Solid-state ~2H NMR relaxation illuminates functional dynamics of retinal cofactor in membrane activation of rhodopsin
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Solid-state ~2H NMR relaxation illuminates functional dynamics of retinal cofactor in membrane activation of rhodopsin

机译：固态〜2H NMR弛豫阐明了视紫红质膜活化中视网膜辅因子的功能动力学

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摘要

Rhodopsin is a canonical member of the family of G protein-coupled receptors, which transmit signals across cellular membranes and are linked to many drug interventions in humans. Here we show that solid-state ~2H NMR relaxation allows investigation of light-induced changes in local ps-ns time scale motions of retinal bound to rhodopsin. Site-specific ~2H labels were introduced into methyl groups of the retinal ligand that are essential to the activation process. We conducted solid-state ~2H NMR relaxation (spin-lattice, T_(1z), and quadrupolar-order, T_(1Q)) experiments in the dark, Meta I, and Meta II states of the photoreceptor. Surprisingly, we find the retinylidene methyl groups exhibit site-specific differences in dynamics that change upon light excitation—even more striking, the C9-methyl group is a dynamical hotspot that corresponds to a crucial functional hotspot of rhodopsin. Following 11-c/s to trans isomerization, the ~2H NMR data suggest the β-ionone ring remains in its hydrophobic binding pocket in all three states of the protein. We propose a multiscale activation mechanism with a complex energy landscape, whereby the photonic energy is directed against the E2 loop by the C13-methyl group, and toward helices H3 and H5 by the C5-methyl of the β-ionone ring. Changes in retinal structure and dynamics initiate activating fluctuations of transmembrane helices H5 and H6 in the Meta I-Meta II equilibrium of rhodopsin. Our proposals challenge the Standard Model whereby a single light-activated receptor conformation yields the visual response —rather an ensemble of substates is present, due to the entropy gain produced by photolysis of the inhibitory retinal lock.
机译：视紫红质是G蛋白偶联受体家族的一个典型成员，该受体跨细胞膜传输信号，并与许多人类药物干预相关。在这里，我们显示固态〜2H NMR弛豫允许研究光结合视紫红质的视网膜局部ps-ns时标运动的光诱导变化。将位点特异的〜2H标签引入到视网膜配体的甲基中，这对于激活过程至关重要。我们在感光器的暗，Meta I和Meta II状态下进行了固态〜2H NMR弛豫（自旋晶格T_（1z）和四极级T_（1Q））实验。出乎意料的是，我们发现视黄叉基甲基在光激发后会发生动力学变化，因此存在特定位置的差异，甚至更令人震惊的是，C9-甲基是一个动态热点，与视紫红质的关键功能性热点相对应。经过11-c / s反式异构化后，〜2H NMR数据表明，β-紫罗兰酮环在蛋白质的所有三种状态下均保留在其疏水结合口袋中。我们提出了一种具有复杂能量格局的多尺度激活机制，其中光子能量通过C13-甲基指向E2环，并通过β-紫罗兰酮环的C5-甲基指向螺旋H3和H5。视紫红质的Meta I-Meta II平衡中，视网膜结构和动力学的变化引发跨膜螺旋H5和H6的激活波动。我们的建议对标准模型提出了挑战，在该模型中，单一的光激活受体构象会产生视觉反应-由于抑制性视网膜锁定的光解产生了熵增益，因此存在大量的亚状态。

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  • 作者

    Andrey V. Struts; Gilmar F. J. Salgado; Michael F. Brown;

  • 作者单位

    Department of Chemistry, University of Arizona, Tucson, AZ 85721,Department of Physics, St. Petersburg State University, St. Petersburg 198904,Russia;

    Laboratoire ARNA, Institut National de la Sante et de la Recherche Medicale (INSERM) U869, Institut Europeen de Chemie et Biologie(IECB),Universite de Bordeaux, F-33000 Bordeaux, France;

    Department of Chemistry, University of Arizona, Tucson, AZ 85721,Department of Physics, University of Arizona, Tucson, AZ 85721;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    GPCR; solid-state NMR; generalized model-free analysis;

    机译：GPCR;固态NMR广义无模型分析;

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