每周论文更新----28 Oct 2016
每周论文更新----28 Oct 2016周伯通博士
本周推送两篇文章，分别来自Cell杂志和其旗下的Neuron杂志。文章的题目分别为："Crystal structure of the human cannabinoid receptor CB1" 和 "Clustering and functional coupling of diverse ion channels and signaling proteins revealed by super-resolution STORM microscopy in neurons"。第一篇Crystal structure of the human cannabinoid receptor CB1人大麻素CB1受体的晶体结构Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, Zhao S, Shui W, Li S, Korde A, Laprairie RB, Stahl EL, Ho JH, Zvonok N, Zhou H, Kufareva I, Wu B, Zhao Q, Hanson MA, Bohn LM, Makriyannis A, Stevens RC, Liu ZJ.Cell. 2016 Oct 20PMID: 27768894AbstractCannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structureof human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.
全文链接：http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(16)31385-X近几年，随着冷冻电镜的应用，结构生物学领域蛋白质结构解析的工作推进的很快。在疼痛领域，一些疼痛相关的蛋白质包括离子通道，G蛋白偶联受体结构的解析也几乎每年都有报道。蛋白质结构解析的一个很重要的贡献就是促进更合理的药物的开发。我们疼痛研究论坛之前报道的一篇基于Mu阿片受体结构的解析而开发的副作用更小的阿片类镇痛药物的文章就属于这一范畴（8月19日那一期）。本篇文章对于人体大麻素CB1受体结构的解析工作做到了2.8个埃（分辨率很高），同时还探讨了CB1受体与其一个拮抗剂AM6538的结合模式。这种模式呈现一种非共价的紧密结合方式，这种紧密结合的模式可能为开发长效缓释药物提供重要的线索。现在，在蛋白质结构解析领域里，中国科研人员参与的越来越多，而且做的也非常的好，本篇文章的第一作者单位就来自于上海科技大学，可喜可贺。
第二篇Clustering and Functional Coupling of Diverse Ion Channels and Signaling Proteins Revealed by Super-resolution STORM Microscopy in Neurons利用超分辨率的STORM显微镜聚类和功能联系性分析神经元上不同的离子通道和信号蛋白Zhang J, Carver CM, Choveau FS, Shapiro MS.Neuron. 2016 Oct 19PMID: 27693258AbstractThe fidelity of neuronal signaling requires organization of signaling molecules into macromolecular complexes, whose components are in intimate proximity. The intrinsic diffraction limit of light makes visualization of individual signaling complexes using visible light extremely difficult. However, using super-resolution stochastic optical reconstruction microscopy (STORM), we observed intimate association of individual molecules within signaling complexes containing ion channels (M-type K+, L-type Ca2+, or TRPV1 channels) and G protein-coupled receptors coupled by the scaffolding protein A-kinase-anchoring protein (AKAP)79/150. Some channels assembled as multi-channel supercomplexes. Surprisingly, we identified novel layers of interplay within macromolecular complexes containing diverse channel types at the single-complex level in sensory neurons, dependent on AKAP79/150. Electrophysiological studies revealed that such ion channels are functionally coupled as well. Our findings illustrate the novel role of AKAP79/150 as a molecular coupler of different channels that conveys crosstalk between channel activities within single microdomains in tuning the physiological response of neurons.
全文链接：http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(16)30573-6哈佛的庄小威想必大家都知道，中科大少年班，40岁就当选美国科学院院士，非常年轻有才华的一位女科学家。她发明的storm显微技术曾竞争过2014年的Nobel化学奖，虽然最后没有评上，但至少可以看的出来她的工作是诺奖级的。我们知道光学显微镜有一个显微极限，专业术语叫衍射极限。衍射极限就是，由于光的衍射特性，一个物点发出的光会形成一个弥散斑，当二个物点靠近的时候，达到一定程度就不能再区分开来，通常200 nm光学显微镜就分辨不出来了，这是它的分辨率极限。200 nm对于分辨一个细胞或者神经元来说已经够了，但是如果要分辨蛋白质则远远不够。庄小威的storm显微技术则将200 nm的显微极限推进到数十纳米，甚至十多纳米左右，这对于推进蛋白质的分辨起到非常大的作用。本文作者主要就是利用storm显微技术研究了神经元内蛋白质复合体的组成，他发现以AKAP79/150支架蛋白为核心的蛋白质复合体组分中包含一系列的离子通道，受体，激酶等等。
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