DOI: 10.1073/pnas.1800756115
论文题名: Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor
作者: Miao Y. ; McCammon J.A.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2018
卷: 115, 期: 12 起始页码: 3036
结束页码: 3041
语种: 英语
英文关键词: Biomolecular recognition
; Enhanced sampling
; GPCR signaling
; Pathways
; Protein binding
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
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. Citation statistics:
资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163735
Appears in Collections: 气候变化与战略
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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
Recommended Citation:
Miao Y.,McCammon J.A.. Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor[J]. Proceedings of the National Academy of Sciences of the United States of America,2018-01-01,115(12)