气候变化领域集成服务门户(CCPortal): Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1

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DOI	10.1073/pnas.1811066116
	Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1
	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.
发表日期	2019
ISSN	0027-8424
起始页码	7123
结束页码	7128
卷号	116 期号:14
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.
英文关键词	Allosteric modulator; Free fatty acid receptor 1; GPCR; Molecular dynamics; Virtual screening
语种	英语
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
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/160372
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 Ce...
推荐引用方式 GB/T 7714	Lückmann M.,Trauelsen M.,Bentsen M.A.,et al. Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1[J],2019,116(14).
APA	Lückmann M..,Trauelsen M..,Bentsen M.A..,Nissen T.A.D..,Martins J..,...&Frimurer T.M..(2019).Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1.Proceedings of the National Academy of Sciences of the United States of America,116(14).
MLA	Lückmann M.,et al."Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1".Proceedings of the National Academy of Sciences of the United States of America 116.14(2019).