气候变化领域集成服务门户(CCPortal): Diverse GPCRs exhibit conserved water networks for stabilization and activation

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DOI	10.1073/pnas.1809251116
	Diverse GPCRs exhibit conserved water networks for stabilization and activation
	Venkatakrishnan A.J.; Ma A.K.; Fonseca R.; Latorraca N.R.; Kelly B.; Betz R.M.; Asawa C.; Kobilka B.K.; Dror R.O.
发表日期	2019
ISSN	0027-8424
起始页码	3288
结束页码	3293
卷号	116 期号:8
英文摘要	G protein-coupled receptors (GPCRs) have evolved to recognize incredibly diverse extracellular ligands while sharing a common architecture and structurally conserved intracellular signaling partners. It remains unclear how binding of diverse ligands brings about GPCR activation, the common structural change that enables intracellular signaling. Here, we identify highly conserved networks of water-mediated interactions that play a central role in activation. Using atomic-level simulations of diverse GPCRs, we show that most of the water molecules in GPCR crystal structures are highly mobile. Several water molecules near the G protein-coupling interface, however, are stable. These water molecules form two kinds of polar networks that are conserved across diverse GPCRs: (i) a network that is maintained across the inactive and the active states and (ii) a network that rearranges upon activation. Comparative analysis of GPCR crystal structures independently confirms the striking conservation of water-mediated interaction networks. These conserved water-mediated interactions near the G protein-coupling region, along with diverse water-mediated interactions with extracellular ligands, have direct implications for structure-based drug design and GPCR engineering. © 2019 National Academy of Sciences. All Rights Reserved.
英文关键词	Activation; GPCR dynamics; Molecular dynamics; Polar network; Simulation; Water molecules
语种	英语
scopus关键词	G protein coupled receptor; ligand; water; G protein coupled receptor; water; Article; comparative study; crystal structure; crystallography; intracellular signaling; ligand binding; priority journal; protein interaction; simulation; chemistry; human; protein conformation; signal transduction; stretching exercise; structure activity relation; X ray crystallography; Crystallography, X-Ray; Humans; Ligands; Muscle Stretching Exercises; Protein Conformation; Receptors, G-Protein-Coupled; Signal Transduction; Structure-Activity Relationship; Water
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160375
作者单位	Venkatakrishnan, A.J., Department of Computer Science, Stanford University, Stanford, CA 94305, United States, Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, United States, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, United States, Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, United States; Ma, A.K., Department of Computer Science, Stanford University, Stanford, CA 94305, United States, Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, United States, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, United States, Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, United States; Fonseca, R., Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanfor...
推荐引用方式 GB/T 7714	Venkatakrishnan A.J.,Ma A.K.,Fonseca R.,et al. Diverse GPCRs exhibit conserved water networks for stabilization and activation[J],2019,116(8).
APA	Venkatakrishnan A.J..,Ma A.K..,Fonseca R..,Latorraca N.R..,Kelly B..,...&Dror R.O..(2019).Diverse GPCRs exhibit conserved water networks for stabilization and activation.Proceedings of the National Academy of Sciences of the United States of America,116(8).
MLA	Venkatakrishnan A.J.,et al."Diverse GPCRs exhibit conserved water networks for stabilization and activation".Proceedings of the National Academy of Sciences of the United States of America 116.8(2019).