GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures.
GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures.
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DOI：
10.1038/nrd.2018.180
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Wüthrich K
中科院分区：
文献类型：
--
作者：
Shimada I;Ueda T;Kofuku Y;Eddy MT;Wüthrich K
人类蛋白质组中的826个G蛋白偶联受体（GPCR）调节关键的生理过程，因此长期以来一直是有吸引力的药物靶点。在过去的十年中，随着超过50种不同的人类GPCR的晶体结构测定，已经为靶向GPCR的药物建立了基于结构的合理设计的初始平台，目前正在用更高阶GPCR复合物的cryo-EM结构来增强。溶液中的核磁共振（NMR）光谱是扩展具有动态特征的该平台的关键方法之一，其可以在生理温度下访问并且对野生型GPCR共价结构进行最小的修改。在这里，我们审查战略使用先进的生物化学和NMR技术与GPCR，调查项目，晶体或冷冻EM结构已补充与NMR调查，并讨论这种综合方法对GPCR生物学和药物发现的影响。美国食品和药物管理局批准的所有药物中有30%以上针对G蛋白偶联受体（GPCR），这些药物用于广泛的治疗领域，包括中枢神经系统以及心血管、呼吸和胃肠道系统的炎症和疾病。目前有300多种药物正在进行临床试验，其中约60种针对新型GPCR，但尚未批准任何药物。新的GPCR靶标还包括孤儿GPCR，尚未发现其内源性配体。总体而言，迄今为止批准的药物仅针对27%的人类非嗅觉GPCR，这表明未来仍有很多令人兴奋的事情。鉴定新的GPCR药物将需要GPCR生物学的额外详细知识，特别是结构生物学知识，因为GPCR信号传导涉及复杂的结构-功能关系。沿着这条线，最近对GPCR的评论涵盖了抗体和纳米抗体的研究，变构调节偏置信号，GPCR结构生物学方法，GPCR晶体结构和药物开发，其中一些评论涉及特定的GPCR家族。补充了大量的GPCR晶体结构，已成为在过去十年中，以及最近的展示的潜力，冷冻-EM提供信息的高阶GPCR复合物，动态研究GPCR是重要的提供新的见解GPCR生物学，可以帮助药物发现。在这方面，溶液中的核磁共振（NMR）光谱是用于分析GPCR中与功能相关的构象平衡的关键工具，因为它们涉及GPCR配体的变构偶联、可变功效和偏置信号传导，这对于它们作为药物的潜力特别感兴趣。此外，NMR光谱也是一个有用的工具，用于基于片段的铅发现与GPCR的目标。在这篇文章中，我们首先概述了GPCR的结构生物学的基础上的知识，从X射线晶体学，冷冻EM和溶液NMR，然后专注于溶液NMR的应用，以加强对GPCR生物学的理解相关的药物发现，以及在基于片段的铅发现。固态NMR研究在GPCR和其他膜蛋白结构的研究中也很有价值，但已在其他地方进行了综述，在此不作介绍。
The 826 G protein-coupled receptors (GPCRs) in the human proteome regulate key physiological processes, and thus have long been attractive as drug targets. With crystal structure determinations of more than 50 different human GPCRs during the last decade, an initial platform for structure-based rational design has been established for drugs that target GPCRs, which is currently being augmented with cryo-EM structures of higher-order GPCR complexes. Nuclear magnetic resonance (NMR) spectroscopy in solution is one of the key approaches for expanding this platform with dynamic features, which can be accessed at physiological temperature and with minimal modification of the wild-type GPCR covalent structures. Here, we review strategies for the use of advanced biochemistry and NMR techniques with GPCRs, survey projects where crystal or cryo-EM structures have been complemented with NMR investigations, and discuss the impact of this integrative approach on GPCR biology and drug discovery. More than 30% of all drugs approved by the US Food and Drug Administration target G protein-coupled receptors (GPCRs), and these drugs are utilized in a wide range of therapeutic areas, including inflammation and diseases of the central nervous system as well as the cardiovascular, respiratory and gastrointestinal systems. Currently more than 300 agents are in clinical trials, of which around 60 target novel GPCRs for which no drug has as yet been approved. The novel GPCR targets also include orphan GPCRs, for which endogenous ligands have not yet been discovered. Overall, the drugs approved so far target only 27% of the human non-olfactory GPCRs, indicating that much excitement still lies ahead. Identifying new GPCR drugs will need additional detailed knowledge of GPCR biology, especially knowledge from structural biology, given the complex structure–function relationships involved in GPCR signaling. Along this line, recent reviews on GPCRs have covered studies with antibodies and nanobodies, allosteric modulation biased signaling, methods in GPCR structural biology, GPCR crystal structures and drug development, with some reviews addressing specific GPCR families. Complementing the substantial number of GPCR crystal structures that have become available in the past decade, as well as the recent demonstrations of the potential for cryo-EM to provide information on higher-order GPCR complexes, dynamic studies of GPCRs are important for providing new insights into GPCR biology that can assist drug discovery. In this respect, nuclear magnetic resonance (NMR) spectroscopy in solution is a key tool for analysing function-related conformational equilibria in GPCRs as they relate to allosteric coupling, variable efficacies and biased signaling of GPCR ligands, which are of particular interest for their potential as drugs. Furthermore, NMR spectroscopy is also a useful tool for fragment-based lead discovery with GPCR targets. In this article, we first overview the structural biology of GPCRs based on knowledge from X-ray crystallography, cryo-EM and solution NMR, and then focus on the application of solution NMR to enhance understanding of GPCR biology relevant to drug discovery, as well as in fragment-based lead discovery. Solid-state NMR studies can also be valuable in the study of GPCR and other membrane protein structures, but have been reviewed elsewhere and are not covered here.
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影响因子：
4.8
作者：
Bayburt, Timothy H.;Vishnivetskiy, Sergey A.;Gurevich, Vsevolod V.
通讯作者：
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DOI：
10.1126/science.1198542
发表时间：
2011-04-08
期刊：
Science (New York, N.Y.)
影响因子：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
64.8
作者：
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DOI：
10.1073/pnas.0900908106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Bajaj, Vikram S.;Mak-Jurkauskas, Melody L.;Griffin, Robert G.
通讯作者：
Griffin, Robert G.