globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1921851117
论文题名:
A combined activation mechanism for the glucagon receptor
作者: Mattedi G.; Acosta-Gutiérrez S.; Clark T.; Gervasio F.L.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2020
卷: 117, 期:27
起始页码: 15414
结束页码: 15422
语种: 英语
英文关键词: Activation ; Enhanced sampling ; Glucagon receptor ; GPCR
Scopus关键词: G protein coupled receptor ; glucagon receptor ; glucagon ; glucagon receptor ; guanine nucleotide binding protein ; allosterism ; amino terminal sequence ; Article ; conformational transition ; crystal structure ; human ; intracellular space ; molecular dynamics ; priority journal ; protein protein interaction ; regulatory mechanism ; cell membrane ; drug design ; metabolism ; protein domain ; structure activity relation ; X ray crystallography ; Allosteric Regulation ; Cell Membrane ; Crystallography, X-Ray ; Drug Design ; Glucagon ; GTP-Binding Proteins ; Molecular Dynamics Simulation ; Protein Domains ; Receptors, Glucagon ; Structure-Activity Relationship
英文摘要: We report on a combined activation mechanism for a class B Gprotein-coupled receptor (GPCR), the glucagon receptor. By computing the conformational free-energy landscape associated with the activation of the receptor-agonist complex and comparing it with that obtained with the ternary complex (receptor-agonist-G protein) we show that the agonist stabilizes the receptor in a preactivated complex, which is then fully activated upon binding of the G protein. The proposed mechanism contrasts with the generally assumed GPCR activation mechanism, which proceeds through an opening of the intracellular region allosterically elicited by the binding of the agonist. The mechanism found here is consistent with electron cryo-microscopy structural data and might be general for class B GPCRs. It also helps us to understand the mode of action of the numerous allosteric antagonists of this important drug target. © 2020 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/163444
Appears in Collections:气候变化与战略

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作者单位: Mattedi, G., Department of Chemistry, University College London, London, WC1E 6BT, United Kingdom; Acosta-Gutiérrez, S., Department of Chemistry, University College London, London, WC1E 6BT, United Kingdom; Clark, T., Computer-Chemistry Center, Department of Chemistry and Pharmacy, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, 91052, Germany; Gervasio, F.L., Department of Chemistry, University College London, London, WC1E 6BT, United Kingdom, Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom, Pharmaceutical Sciences, University of Geneva, Geneva, CH-1211, Switzerland

Recommended Citation:
Mattedi G.,Acosta-Gutiérrez S.,Clark T.,et al. A combined activation mechanism for the glucagon receptor[J]. Proceedings of the National Academy of Sciences of the United States of America,2020-01-01,117(27)
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