气候变化领域集成服务门户(CCPortal): A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- And heterodimers

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DOI	10.1073/pnas.2105848118
	A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- And heterodimers
	Haubrich J.; Font J.; Quast R.B.; Goupil-Lamy A.; Scholler P.; Nevoltris D.; Acher F.; Chames P.; Rondard P.; Prézeau L.; Pin J.-P.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:33
英文摘要	There is growing interest in developing biologics due to their high target selectivity. The G protein-coupled homo- and heterodimeric metabotropic glutamate (mGlu) receptors regulate many synapses and are promising targets for the treatment of numerous brain diseases. Although subtype-selective allosteric small molecules have been reported, their effects on the recently discovered heterodimeric receptors are often not known. Here, we describe a nanobody that specifically and fully activates homodimeric human mGlu4 receptors. Molecular modeling and mutagenesis studies revealed that the nanobody acts by stabilizing the closed active state of the glutamate binding domain by interacting with both lobes. In contrast, this nanobody does not activate the heterodimeric mGlu2-4 but acts as a pure positive allosteric modulator. These data further reveal how an antibody can fully activate a class C receptor and bring further evidence that nanobodies represent an alternative way to specifically control mGlu receptor subtypes. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Activation mechanism; Agonist; G protein-coupled receptor; Single-domain antibody
语种	英语
scopus关键词	heterodimer; homodimer; metabotropic receptor 2; metabotropic receptor 3; metabotropic receptor 4; nanobody; metabotropic receptor; metabotropic receptor 4; nanobody; protein binding; allosterism; animal cell; animal experiment; antigen binding; Article; binding affinity; conformation; controlled study; Escherichia coli; flow cytometry; glutamate binding domain; human; human cell; llama; molecular model; mutagenesis; nonhuman; protein structure; rat; biological model; drug effect; gene expression regulation; genetics; metabolism; mutation; protein conformation; Gene Expression Regulation; Humans; Models, Biological; Mutation; Protein Binding; Protein Conformation; Receptors, Metabotropic Glutamate; Single-Domain Antibodies
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/251053
作者单位	Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier Cedex 5, 34094, France; Centre de Biologie Structurale, University of Montpellier, CNRS, INSERM, Montpellier, 34090, France; BIOVIA Science Council, Dassault Système, Vélizy-Villacoublay Cedex, F-78140, France; Institut Paoli-Calmettes, Aix Marseille University, CNRS, INSERM, Centre de Recherche en Cancérologie de Marseille, Marseille, 13009, France; Faculté des Sciences Fondamentales et Biomédicales, Université de Paris, CNRS, Paris Cedex 06, 75270, France
推荐引用方式 GB/T 7714	Haubrich J.,Font J.,Quast R.B.,et al. A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- And heterodimers[J],2021,118(33).
APA	Haubrich J..,Font J..,Quast R.B..,Goupil-Lamy A..,Scholler P..,...&Pin J.-P..(2021).A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- And heterodimers.Proceedings of the National Academy of Sciences of the United States of America,118(33).
MLA	Haubrich J.,et al."A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- And heterodimers".Proceedings of the National Academy of Sciences of the United States of America 118.33(2021).