<br>GPCR介导的抑制蛋白激活的分子机制,Nature

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GPCR介导的抑制蛋白激活的分子机制
Nature ( IF 50.5 ) Pub Date : 2018-05-01 , DOI: 10.1038/s41586-018-0077-3
Naomi R Latorraca _{1,

2,

3,

4} , Jason K Wang ₂ , Brian Bauer ₅ , Raphael J L Townshend ₂ , Scott A Hollingsworth _{1,

2,

3} , Julia E Olivieri ₄ , H Eric Xu _{6,

7} , Martha E Sommer ₅ , Ron O Dror _{1,

2,

3,

4}

Affiliation

尽管人们对发现导致 G 蛋白偶联受体 (GPCR) 选择性刺激或阻断抑制蛋白信号传导的药物抱有浓厚兴趣，但受体介导的抑制蛋白激活的结构机制仍不清楚1,2。在这里，我们通过广泛的视紫红质抑制蛋白的原子级模拟揭示了这种机制。我们发现受体的跨膜核心和细胞质尾部（结合视紫红质抑制蛋白的不同表面）可以各自独立地刺激视紫红质抑制蛋白激活。我们使用定点荧光光谱证实了受体核心的这种意想不到的作用，以及视紫红质抑制蛋白这些遥远表面之间的变构耦合。受体核心对视紫红质抑制蛋白构象的影响主要是通过受体的细胞内环与视紫红质抑制蛋白体的相互作用介导的，而不是在受体结合时观察到的明显的指环重排。在没有受体的情况下，视紫红质抑制蛋白在其自身的 C 末端尾部脱离时经常采取活性构象，这可以解释为什么某些视紫红质抑制蛋白在受体解离后很长时间仍保持活性。我们的结果表明，不同的受体结合模式可以激活视紫红质抑制蛋白，为设计功能选择性（“偏向”）GPCR 靶向配体提供了结构基础，对视紫红质抑制蛋白信号传导产生所需的影响。分子动力学模拟和定点荧光光谱显示G蛋白偶联受体的跨膜核心和胞质尾独立并协同激活视紫红质抑制蛋白。

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Molecular mechanism of GPCR-mediated arrestin activation

Despite intense interest in discovering drugs that cause G-protein-coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated arrestin activation remains unclear1,2. Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor’s transmembrane core and cytoplasmic tail—which bind distinct surfaces on arrestin—can each independently stimulate arrestin activation. We confirm this unanticipated role of the receptor core, and the allosteric coupling between these distant surfaces of arrestin, using site-directed fluorescence spectroscopy. The effect of the receptor core on arrestin conformation is mediated primarily by interactions of the intracellular loops of the receptor with the arrestin body, rather than the marked finger-loop rearrangement that is observed upon receptor binding. In the absence of a receptor, arrestin frequently adopts active conformations when its own C-terminal tail is disengaged, which may explain why certain arrestins remain active long after receptor dissociation. Our results, which suggest that diverse receptor binding modes can activate arrestin, provide a structural foundation for the design of functionally selective (‘biased’) GPCR-targeted ligands with desired effects on arrestin signalling.Molecular dynamics simulations and site-directed fluorescence spectroscopy show that the transmembrane core and cytoplasmic tail of G-protein-coupled receptors independently and cooperatively activate arrestin.

更新日期：2018-05-01

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