Retinal dynamics underlie its switch from inverse agonist to agonist during rhodopsin activation.
Retinal dynamics underlie its switch from inverse agonist to agonist during rhodopsin activation.
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DOI：
10.1038/nsmb.1982
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发表时间：
2011-03
影响因子：
16.8
通讯作者：
Brown MF
中科院分区：
文献类型：
--
作者：
Struts AV;Salgado GF;Martínez-Mayorga K;Brown MF
在寻求了解 G 蛋白偶联受体 (GPCR) 介导的信号传导过程中，X 射线和磁共振方法发挥了重要作用，但 GPCR 的蛋白质动力学和可塑性均不适合研究。在这里，我们证明固态 2H NMR 弛豫阐明了视网膜配体的皮秒-纳秒时间尺度运动，这些运动影响膜中视紫红质的更大规模功能动力学。提出了一种多尺度激活机制，视网膜在微秒-毫秒时间尺度上启动 Meta I-Meta II 平衡中的集体螺旋波动。视紫红质是 G 蛋白偶联受体 (GPCR) 的重要原型，GPCR 参与生物信号传导并构成许多人类药物靶标。配体的结构如何与更大规模的功能蛋白动力学联系起来仍然难以捉摸。固态核磁共振弛豫表明，视网膜的局部运动导致光感受器激活机制中跨膜螺旋的集体波动。
In seeking to understand G protein-coupled receptor (GPCR)-mediated signaling, X-ray and magnetic resonance approaches have played important roles—yet neither the protein dynamics nor the plasticity of GPCRs are amenable to study. Here we show that solid-state 2H NMR relaxation elucidates picosecond-nanosecond timescale motions of the retinal ligand that impact upon larger-scale functional dynamics of rhodopsin in membranes. A multiscale activation mechanism is put forward, whereby retinal initiates collective helix fluctuations in the Meta I–Meta II equilibrium on the microsecond-millisecond timescale. Rhodopsin is an important prototype for G protein-coupled receptors (GPCRs) that are implicated in biological signaling and constitute many human pharmaceutical targets. How the structure of the ligand is connected with larger-scale functional protein dynamics has remained elusive. Solid-state NMR relaxation shows that localized motions of retinal lead to collective fluctuations of transmembrane helices in the activation mechanism of the photoreceptor.