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DOI | 10.1038/s41586-020-2408-4 |
Structural basis of the activation of a metabotropic GABA receptor | |
Montagne, Axel1; 39;Orazio, Lina M.2 | |
2020-04-29 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2020 |
文章类型 | Article;Early Access |
语种 | 英语 |
国家 | USA; France |
英文关键词 | Metabotropic gamma-aminobutyric acid receptors (GABA(B)) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis(1). GABA(B)belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits(2). Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1-GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABA(B). Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface. Cryo-electron microscopy structures of apo, agonist- and positive allosteric modulator-bound forms of the GB1-GB2 heterodimer of the metabotropic gamma-aminobutyric acid (GABA) receptor shed light on the activation mechanism of this receptor. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000541024900003 |
WOS关键词 | ALLOSTERIC INTERACTIONS ; SOFTWARE NEWS ; PHARMACOLOGY ; MUTATIONS ; BACLOFEN ; SUBUNITS ; GS39783 ; STATE ; MGLU ; GB2 |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/281561 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Univ Southern Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Physiol & Neurosci, Los Angeles, CA 90007 USA; 2.Univ Southern Calif, Keck Sch Med, Alzheimers Dis Res Ctr, Los Angeles, CA 90007 USA; 3.Univ Calif Irvine, Dept Psychol Sci, Irvine, CA USA; 4.Univ Calif Irvine, Inst Memory Disorders & Neurol Impairments, Irvine, CA USA; 5.Univ Southern Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90007 USA; 6.Huntington Med Res Inst, Pasadena, CA USA; 7.Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA; 8.Washington Univ, Sch Med, Hope Ctr Neurodegenerat Disorders, St Louis, MO USA; 9.Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA; 10.Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, St Louis, MO USA; 11.Univ Southern Calif, Dept Psychiat & Behav Sci, Los Angeles, CA 90007 USA; 12.Banner Alzheimer Inst, Phoenix, AZ USA; 13.Mayo Clin, Dept Neurol, Scottsdale, AZ USA; 14.Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA; 15.Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA; 16.Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, New York, NY 10029 USA; 17.Univ Southern Calif, Keck Sch Med, USC Stevens Neuroimaging & Informat Inst, Lab Neuroimaging, Los Angeles, CA 90007 USA; 18.Univ Southern Calif, Keck Sch Med, Dept Radiol, Mol Imaging Ctr, Los Angeles, CA 90007 USA; 19.Univ Southern Calif, Keck Sch Med, Dept Neurol Surg, Los Angeles, CA 90007 USA; 20.Monash Univ, Alfred Hlth, Dept Neurosci & Radiol, Melbourne, Vic, Australia |
推荐引用方式 GB/T 7714 | Montagne, Axel,39;Orazio, Lina M.. Structural basis of the activation of a metabotropic GABA receptor[J]. NATURE,2020. |
APA | Montagne, Axel,&39;Orazio, Lina M..(2020).Structural basis of the activation of a metabotropic GABA receptor.NATURE. |
MLA | Montagne, Axel,et al."Structural basis of the activation of a metabotropic GABA receptor".NATURE (2020). |
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