G蛋白偶联受体的魔角旋转核磁共振

IF 7.3 2区 化学 Q2 CHEMISTRY, PHYSICAL
Bianca Chandler, Lauren Todd, Steven O. Smith
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引用次数: 3

摘要

G蛋白偶联受体(gpcr)具有简单的七跨膜螺旋结构,已进化到识别多种化学信号。人类基因组中编码的800多个gpcr作为视觉、嗅觉和味觉的受体,并介导关键的生理过程。因此,这些受体是药物的主要靶点。蛋白质晶体学和电子冷冻显微镜已经提供了许多gpcr活性和非活性构象的高分辨率结构。然而,这些结构并没有引发合理药物设计的高潮,部分原因是gpcr本身是动态的,并且配体或药物结合引起的结构变化通常是在包装或氢键相互作用中微妙的重排。核磁共振波谱提供了一个敏感的探针局部结构和动力学在这些受体内的特定位点以及受体结构和动力学的整体变化。这些方法还可以捕获中间状态和低种群的构象,从而深入了解激活途径。我们回顾了使用固态魔角自旋核磁共振来解决gpcr的结构和激活机制。重点是大而多样的A类受体家族。我们重点介绍了三种特定的A类GPCR,以说明固态和溶液状态,核磁共振波谱可以回答涉及不同GPCR类别和亚家族如何被其相关配体激活的领域的问题,以及小分子药物如何调节GPCR的激活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Magic angle spinning NMR of G protein-coupled receptors

Magic angle spinning NMR of G protein-coupled receptors

G protein-coupled receptors (GPCRs) have a simple seven transmembrane helix architecture which has evolved to recognize a diverse number of chemical signals. The more than 800 GPCRs encoded in the human genome function as receptors for vision, smell and taste, and mediate key physiological processes. Consequently, these receptors are a major target for pharmaceuticals. Protein crystallography and electron cryo-microscopy have provided high resolution structures of many GPCRs in both active and inactive conformations. However, these structures have not sparked a surge in rational drug design, in part because GPCRs are inherently dynamic and the structural changes induced by ligand or drug binding to stabilize inactive or active conformations are often subtle rearrangements in packing or hydrogen-bonding interactions. NMR spectroscopy provides a sensitive probe of local structure and dynamics at specific sites within these receptors as well as global changes in receptor structure and dynamics. These methods can also capture intermediate states and conformations with low populations that provide insights into the activation pathways. We review the use of solid-state magic angle spinning NMR to address the structure and activation mechanisms of GPCRs. The focus is on the large and diverse class A family of receptors. We highlight three specific class A GPCRs in order to illustrate how solid-state, as well as solution-state, NMR spectroscopy can answer questions in the field involving how different GPCR classes and subfamilies are activated by their associated ligands, and how small molecule drugs can modulate GPCR activation.

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来源期刊
CiteScore
14.30
自引率
8.20%
发文量
12
审稿时长
62 days
期刊介绍: Progress in Nuclear Magnetic Resonance Spectroscopy publishes review papers describing research related to the theory and application of NMR spectroscopy. This technique is widely applied in chemistry, physics, biochemistry and materials science, and also in many areas of biology and medicine. The journal publishes review articles covering applications in all of these and in related subjects, as well as in-depth treatments of the fundamental theory of and instrumental developments in NMR spectroscopy.
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