Molecular simulations and solid-state NMR investigate dynamical structure in rhodopsin activation.
Molecular simulations and solid-state NMR investigate dynamical structure in rhodopsin activation.
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分子模拟和固态核磁共振研究视紫红质激活的动态结构。
DOI：
10.1016/j.bbamem.2011.08.003
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Brown,MichaelF
中科院分区：
文献类型：
--
作者：
Mertz,Blake;Struts,AndreyV;Feller,ScottE;Brown,MichaelF
视紫红质已成为研究 G 蛋白偶联受体 (GPCR) 的主要模型，GPCR 是人类基因组中最大的群体，因此也是药物开发的主要目标。事实证明，了解 GPCR 的功能和激活机制非常困难，因为它们是复杂信号级联的一部分，并且存在于细胞膜内。尽管 X 射线晶体学最近已经解析了几种可能类似于激活构象的 GPCR 结构，但视紫红质激活的动力学和机制仍然难以捉摸。值得注意的是，固态 2 H NMR 光谱提供了与视紫红质激活过程中视网膜配体局部动力学如何变化相关的关键信息。当与蛋白脂质膜的分子力学模拟相结合时，出现了视紫红质激活过程的新范例。实验和模拟都表明，视网膜异构化启动视紫红质光级联产生的不是单一的激活结构，而是一组激活的构象状态。本文是题为“膜蛋白结构和功能”的特刊的一部分。
Rhodopsin has served as the primary model for studying G protein-coupled receptors (GPCRs)—the largest group in the human genome, and consequently a primary target for pharmaceutical development. Understanding the functions and activation mechanisms of GPCRs has proven to be extraordinarily difficult, as they are part of a complex signaling cascade and reside within the cell membrane. Although X-ray crystallography has recently solved several GPCR structures that may resemble the activated conformation, the dynamics and mechanism of rhodopsin activation continue to remain elusive. Notably solid-state2H NMR spectroscopy provides key information pertinent to how local dynamics of the retinal ligand change during rhodopsin activation. When combined with molecular mechanics simulations of proteolipid membranes, a new paradigm for the rhodopsin activation process emerges. Experiment and simulation both suggest that retinal isomerization initiates the rhodopsin photocascade to yield not a single activated structure, but rather an ensemble of activated conformational states. This article is part of a Special Issue entitled: Membrane protein structure and function.