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Structure paper

タイトル	Structures of metabotropic GABA receptor.
ジャーナル・号・ページ	Nature, Vol. 584, Issue 7820, Page 310-314, Year 2020
掲載日	2020年6月24日
著者	Makaía M Papasergi-Scott / Michael J Robertson / Alpay B Seven / Ouliana Panova / Jesper M Mathiesen / Georgios Skiniotis /
PubMed 要旨	Stimulation of the metabotropic GABA receptor by γ-aminobutyric acid (GABA) results in prolonged inhibition of neurotransmission, which is central to brain physiology. GABA belongs to family C of ...Stimulation of the metabotropic GABA receptor by γ-aminobutyric acid (GABA) results in prolonged inhibition of neurotransmission, which is central to brain physiology. GABA belongs to family C of the G-protein-coupled receptors, which operate as dimers to transform synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins. However, GABA is unique in its function as an obligate heterodimer in which agonist binding and G-protein activation take place on distinct subunits. Here we present cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABA receptors. Complemented by cellular signalling assays and atomistic simulations, these structures reveal that extracellular loop 2 (ECL2) of GABA has an essential role in relaying structural transitions by ordering the linker that connects the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of each of the subunits of GABA caps and interacts with the hydrophilic head of a phospholipid that occupies the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G proteins. These results provide a starting framework through which to decipher the mechanistic modes of signal transduction mediated by GABA dimers, and have important implications for rational drug design that targets these receptors.
リンク	Nature / PubMed:32580208 / PubMed Central
手法	EM (単粒子)
解像度	3.2 - 3.6 Å
構造データ	21533 6w2x EMDB-21533, PDB-6w2x: CryoEM Structure of Inactive GABAB Heterodimer 手法: EM (単粒子) / 解像度: 3.6 Å 21534 6w2y EMDB-21534, PDB-6w2y: CryoEM Structure of GABAB1b Homodimer 手法: EM (単粒子) / 解像度: 3.2 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン / N-アセチルグルコサミン ChemComp-L9Q: (1S)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(octadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate / [S,(-)]-1-O-ステアロイル-2-O-オレオイル-D-グリセロ-ル3-(りん酸2-アミノエチル) ChemComp-SGG: [(2~{S})-3-[[(1~{S})-1-(3,4-dichlorophenyl)ethyl]amino]-2-oxidanyl-propyl]-(phenylmethyl)phosphinic acid / CGP-55845A ChemComp-MG: Unknown entry / マグネシウムジカチオン
由来	homo sapiens (ヒト)
キーワード	SIGNALING PROTEIN / Inhibitor / Heterodimer / GPCR (Gタンパク質共役受容体) / Homodimer