globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1811066116
论文题名:
Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1
作者: Lückmann M.; Trauelsen M.; Bentsen M.A.; Nissen T.A.D.; Martins J.; Fallah Z.; Nygaard M.M.; Papaleo E.; Lindorff-Larsen K.; Schwartz T.W.; Frimurer T.M.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2019
卷: 116, 期:14
起始页码: 7123
结束页码: 7128
语种: 英语
英文关键词: Allosteric modulator ; Free fatty acid receptor 1 ; GPCR ; Molecular dynamics ; Virtual screening
Scopus关键词: carboxylic acid ; G protein coupled receptor 40 ; ligand ; solvent ; benzofuran derivative ; FFAR1 protein, human ; G protein coupled receptor ; protein binding ; sulfone ; TAK-875 ; allosterism ; Article ; controlled study ; crystallization ; DNA modification ; drug development ; ligand binding ; molecular docking ; molecular dynamics ; priority journal ; process optimization ; protein function ; protein synthesis ; protein targeting ; signal transduction ; structure analysis ; allosteric site ; allosterism ; antagonists and inhibitors ; binding site ; chemistry ; drug effect ; genetics ; human ; mutation ; protein conformation ; X ray crystallography ; Allosteric Regulation ; Allosteric Site ; Benzofurans ; Binding Sites ; Crystallography, X-Ray ; Humans ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Protein Conformation ; Receptors, G-Protein-Coupled ; Sulfones
英文摘要: The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TMI, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an allosteric modulator of receptor activation. This discovery of an allosteric agonist for a previously unexploited, dynamic pocket in FFAR1 demonstrates both the power of including molecular dynamics in the drug discovery process and that this specific, clinically proven, but difficult, antidiabetes target can be addressed by chemotypes different from existing ligands. © 2019 National Academy of Sciences. All Rights Reserved.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163563
Appears in Collections:气候变化与战略

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作者单位: Lückmann, M., Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DL-2200, Denmark, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark; Trauelsen, M., Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DL-2200, Denmark; Bentsen, M.A., Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DL-2200, Denmark; Nissen, T.A.D., Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DL-2200, Denmark; Martins, J., Department of Biology, University of Copenhagen, Copenhagen, DK-2200, Denmark; Fallah, Z., Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DL-2200, Denmark, School of Nano Science, Institute for Research in Fundamental Sciences, Tehran, 19395-5531, Iran; Nygaard, M.M., Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, DK-2100, Denmark; Papaleo, E., Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, DK-2100, Denmark, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, DK-2200, Denmark; Lindorff-Larsen, K., Department of Biology, University of Copenhagen, Copenhagen, DK-2200, Denmark; Schwartz, T.W., Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DL-2200, Denmark, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark; Frimurer, T.M., Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DL-2200, Denmark, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, DK-2200, Denmark

Recommended Citation:
Lückmann M.,Trauelsen M.,Bentsen M.A.,et al. Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1[J]. Proceedings of the National Academy of Sciences of the United States of America,2019-01-01,116(14)
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