Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jiaqi Hu, Xianqiang Sun, Zhengzhong Kang, Jianxin Cheng
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引用次数: 1

Abstract

G protein-coupled receptors (GPCRs) are membrane proteins constituting the largest family of drug targets. The activated GPCR binds either the heterotrimeric G proteins or arrestin through its activation cycle. Water molecules have been reported to play a role in GPCR activation. Nevertheless, reported studies are focused on the hydrophobic helical bundle region. How water molecules function in GPCR bound either G protein or arrestin is rarely studied. To address this issue, we carried out computational studies on water molecules in both GPCR/G protein complexes and GPCR/arrestin complexes. Using inhomogeneous fluid theory (IFT), we locate all possible hydration sites in GPCRs binding either to G protein or arrestin. We observe that the number of water molecules on the interaction surface between GPCRs and signal proteins are correlated with the insertion depths of the α5-helix from G-protein or “finger loop” from arrestin in GPCRs. In three out of the four simulation pairs, the interfaces of Rhodopsin, M2R and NTSR1 in the G protein-associated systems show more water-mediated hydrogen-bond networks when compared to these in arrestin-associated systems. This reflects that more functionally relevant water molecules may probably be attracted in G protein-associated structures than that in arrestin-associated structures. Moreover, we find the water-mediated interaction networks throughout the NPxxY region and the orthosteric pocket, which may be a key for GPCR activation. Reported studies show that non-biased agonist, which can trigger both GPCR-G protein and GPCR-arrestin activation signal, can result in pharmacologically toxicities. Our comprehensive studies of the hydration sites in GPCR/G protein complexes and GPCR/arrestin complexes may provide important insights in the design of G-protein biased agonists.

Abstract Image

与G蛋白或阻滞蛋白结合的gpcr中功能水分子的计算研究
G蛋白偶联受体(gpcr)是膜蛋白,是最大的药物靶点家族。激活的GPCR通过其激活周期与异源三聚体G蛋白或阻滞蛋白结合。据报道,水分子在GPCR激活中起作用。然而,报道的研究主要集中在疏水螺旋束区域。水分子如何在GPCR结合G蛋白或阻滞蛋白中起作用,目前还很少研究。为了解决这个问题,我们对GPCR/G蛋白复合物和GPCR/阻滞蛋白复合物中的水分子进行了计算研究。利用非均质流体理论(IFT),我们定位了gpcr中与G蛋白或阻滞蛋白结合的所有可能的水合位点。我们观察到gpcr与信号蛋白相互作用表面的水分子数量与gpcr中g蛋白α5-螺旋的插入深度或阻滞蛋白的“手指环”的插入深度相关。在四个模拟对中的三个中,与阻滞蛋白相关系统中的界面相比,G蛋白相关系统中的视紫红质,M2R和NTSR1界面显示出更多的水介导的氢键网络。这反映了在G蛋白相关结构中可能比在阻滞蛋白相关结构中吸引更多功能相关的水分子。此外,我们发现水介导的相互作用网络遍布NPxxY区域和正构口袋,这可能是GPCR激活的关键。已有研究表明,非偏倚激动剂可以同时触发GPCR-G蛋白和gpcr -阻滞素激活信号,从而导致药理学毒性。我们对GPCR/G蛋白复合物和GPCR/抑制蛋白复合物水合位点的综合研究可能为G蛋白偏向性激动剂的设计提供重要的见解。
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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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