The Year In G Protein-Coupled Receptor Research
The Year In G Protein-Coupled Receptor Research
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DOI：
10.1210/me.2009-0473
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发表时间：
2010-01-01
影响因子：
--
通讯作者：
Newton, Claire L.
中科院分区：
文献类型：
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作者：
Millar, Robert P.;Newton, Claire L.
I（R.P.M.）在ENDO 2009上发表了“G蛋白偶联受体研究年度”。我首先描述了配体的多样性和大约800个G蛋白偶联受体（GPCR）的五个家族，它们的基本结构架构，它们在信号传导中的卓越作用，以及开发针对GPCR的药物的巨大范围。然后，我谈到了在解决视紫红质、β（2）-肾上腺素能、β（1）-肾上腺素能和A（2A）-腺苷受体的活性状态的原子水平结构方面的一些令人兴奋的突破。我还描述了对GPCR的视紫红质家族的激活伴随的结构变化的研究。从这些最新的技术进展中，我们可以预期将出现更多的GPCR结构，这将使我们更深入地了解它们的共同和独特的结构特征，特别是它们的激活机制。这些见解将指导我们理解GPCR在正常和病理情况下如何运作。虽然这些晶体结构是高度信息化的，但重要的是要认识到它们代表单一GPCR状态的静态冷冻构象。因此，正在利用新的生物物理技术来促进动态监测与配体活化有关的GPCR结构变化。GPCR的晶体结构的求解也呈现了使用配体结合口袋的信息以允许在计算机上筛选新的小分子配体的真实的可能性。然后，我回顾了配体诱导的GPCR选择性信号传导的概念，这为更具选择性的药物开发提供了新的见解。作为同源和异源寡聚体的GPCR的组装及其磷酸化和与大量的运输和信号调节蛋白的关联正在成为GPCR功能的主要机制。这些蛋白质的差异表达和募集为细胞活性的微妙生理调节提供了机制。最后，我提到了一些最近作为内分泌学中的新型调节剂而脱颖而出的GPCR。这些包括胰腺β细胞中表达的脂肪酸特异性GPCR和调节生殖的新型神经内分泌GPCR。（分子内分泌学24：261-274，2010）
I (R.P.M.) presented "The Year In G Protein-Coupled Receptor Research" at ENDO 2009. I first described the diversity of ligands and the five families into which the approximately 800 G protein-coupled receptors (GPCRs) are grouped, their basic structural architectures, their preeminent role in signaling, and the enormous scope for developing drugs targeted at GPCRs. I then spoke about some of the exciting breakthroughs in solving the atomic level structures of the active state of rhodopsin, beta(2)-adrenergic, beta(1)-adrenergic, and A(2A)-adenosine receptors. I also described studies on the structural changes accompanying the activation of the rhodopsin family of GPCRs. From these recent technical advances, we can anticipate that many more GPCR structures will emerge, which will afford us greater insight into their common and unique structural features and, particularly, the mechanisms underlying their activation. These insights will guide us in our understanding of how GPCRs operate, both in the normal and pathological situation. Although these crystal structures are highly informative, it is important to recognize that they represent static frozen conformations of a single GPCR state. New biophysical techniques are therefore being utilized to facilitate the dynamic monitoring of GPCR structural changes in relation to ligand activation. Solving of the crystal structures of GPCRs has also presented the real possibility of using the information of the ligand-binding pocket to allow in silico screening for novel small-molecule ligands. I then reviewed the concept of ligand-induced selective signaling of GPCRs, which is opening up new insights into more selective drug development. The assembly of GPCRs as homo-and heterooligomers and their phosphorylation and association with a vast array of trafficking and signal-modulating proteins are emerging as major mechanisms underlying the functioning of GPCRs. Differential expression and recruitment of these proteins provide a mechanism for subtle physiological regulation of cellular activity. Finally, I mentioned some of the GPCRs that have lately come to the fore as novel regulators in endocrinology. These included fatty acid-specific GPCRs expressed in pancreatic beta-cells and novel neuroendocrine GPCRs regulating reproduction. (Molecular Endocrinology 24: 261-274, 2010)