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DOI	10.1073/pnas.1800756115
	Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor
	Miao Y.; McCammon J.A.
发表日期	2018
ISSN	0027-8424
起始页码	3036
结束页码	3041
卷号	115 期号:12
英文摘要	Protein-protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein-protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G-protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method. Through long-timescale GaMD simulations over 4,500 ns, the nanobody was observed to bind the receptor intracellular Gprotein- coupling site, with a minimum rmsd of 2.48 Å in the nanobody core domain compared with the X-ray structure. Binding of the nanobody allosterically closed the orthosteric ligand-binding pocket, being consistent with the recent experimental finding. In the absence of nanobody binding, the receptor orthosteric pocket sampled open and fully open conformations. The GaMD simulations revealed two low-energy intermediate states during nanobody binding to the M2 receptor. The flexible receptor intracellular loops contribute remarkable electrostatic, polar, and hydrophobic residue interactions in recognition and binding of the nanobody. These simulations provided important insights into the mechanism of GPCR-nanobody binding and demonstrated the applicability of GaMD in modeling dynamic protein-protein interactions. © 2018 National Academy of Sciences. All Rights Reserved.
英文关键词	Biomolecular recognition; Enhanced sampling; GPCR signaling; Pathways; Protein binding
语种	英语
scopus关键词	G protein mimetic nanobody nb9 8; guanine nucleotide binding protein; muscarinic M2 receptor; muscarinic M2 receptor agonist; unclassified drug; G protein coupled receptor; muscarinic M2 receptor; nanobody; protein binding; allosterism; Article; controlled study; hydrophobicity; ligand binding; molecular dynamics; priority journal; protein binding; protein conformation; protein protein interaction; protein structure; receptor binding; static electricity; chemistry; computer simulation; metabolism; molecular model; physiology; thermodynamics; Computer Simulation; Models, Molecular; Protein Binding; Protein Conformation; Receptor, Muscarinic M2; Receptors, G-Protein-Coupled; Single-Domain Antibodies; Thermodynamics
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/160537
作者单位	Miao, Y., Center for Computational Biology, University of Kansas, Lawrence, KS 66047, United States, Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66047, United States; McCammon, J.A., Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, United States, Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, CA 92093, United States
推荐引用方式 GB/T 7714	Miao Y.,McCammon J.A.. Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor[J],2018,115(12).
APA	Miao Y.,&McCammon J.A..(2018).Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor.Proceedings of the National Academy of Sciences of the United States of America,115(12).
MLA	Miao Y.,et al."Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor".Proceedings of the National Academy of Sciences of the United States of America 115.12(2018).