+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7na7 | |||||||||
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タイトル | Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist | |||||||||
要素 |
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キーワード | MEMBRANE PROTEIN / GPCR / appetite / energy homeostasis / reward signaling | |||||||||
機能・相同性 | 機能・相同性情報 growth hormone secretagogue receptor activity / regulation of hindgut contraction / ghrelin receptor binding / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / regulation of growth hormone secretion / negative regulation of locomotion / growth hormone-releasing hormone receptor activity / cortisol secretion / positive regulation of small intestinal transit ...growth hormone secretagogue receptor activity / regulation of hindgut contraction / ghrelin receptor binding / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / regulation of growth hormone secretion / negative regulation of locomotion / growth hormone-releasing hormone receptor activity / cortisol secretion / positive regulation of small intestinal transit / growth hormone-releasing hormone activity / positive regulation of small intestine smooth muscle contraction / negative regulation of circadian sleep/wake cycle, REM sleep / positive regulation of circadian sleep/wake cycle, non-REM sleep / negative regulation of locomotion involved in locomotory behavior / regulation of response to food / regulation of gastric motility / regulation of transmission of nerve impulse / positive regulation of corticotropin secretion / response to follicle-stimulating hormone / positive regulation of cortisol secretion / growth hormone secretion / ghrelin secretion / gastric acid secretion / positive regulation of growth rate / positive regulation of eating behavior / negative regulation of norepinephrine secretion / positive regulation of appetite / negative regulation of macrophage apoptotic process / adult feeding behavior / positive regulation of growth hormone secretion / negative regulation of appetite / positive regulation of growth hormone receptor signaling pathway / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cellular response to thyroid hormone stimulus / positive regulation of synapse assembly / response to growth hormone / cartilage development / positive regulation of insulin-like growth factor receptor signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / response to food / positive regulation of vascular endothelial cell proliferation / cellular response to insulin-like growth factor stimulus / negative regulation of interleukin-1 beta production / regulation of postsynapse organization / response to L-glutamate / regulation of synapse assembly / positive regulation of fatty acid metabolic process / postsynaptic modulation of chemical synaptic transmission / protein tyrosine kinase activator activity / positive regulation of sprouting angiogenesis / response to dexamethasone / dendrite development / negative regulation of endothelial cell proliferation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / peptide hormone binding / decidualization / negative regulation of tumor necrosis factor production / Synthesis, secretion, and deacylation of Ghrelin / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / negative regulation of insulin secretion / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / response to electrical stimulus / regulation of mitotic spindle organization / cellular response to forskolin / synapse assembly / positive regulation of adipose tissue development / hormone-mediated signaling pathway / response to hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of angiogenesis / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / insulin-like growth factor receptor signaling pathway / excitatory postsynaptic potential / synaptic membrane / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / positive regulation of insulin secretion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Schaffer collateral - CA1 synapse / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) Mus musculus (ハツカネズミ) | |||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.7 Å | |||||||||
データ登録者 | Liu, H. / Sun, D. / Sun, J. / Zhang, C. | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Nat Commun / 年: 2021 タイトル: Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren. 著者: Heng Liu / Dapeng Sun / Alexander Myasnikov / Marjorie Damian / Jean-Louis Baneres / Ji Sun / Cheng Zhang / 要旨: The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its ...The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-G signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the G and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs. | |||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7na7.cif.gz | 209.6 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7na7.ent.gz | 170.8 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7na7.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 7na7_validation.pdf.gz | 801.2 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7na7_full_validation.pdf.gz | 810.5 KB | 表示 | |
XML形式データ | 7na7_validation.xml.gz | 36.6 KB | 表示 | |
CIF形式データ | 7na7_validation.cif.gz | 56.5 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/na/7na7 ftp://data.pdbj.org/pub/pdb/validation_reports/na/7na7 | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 ABG
#1: タンパク質 | 分子量: 40429.059 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNAI1 発現宿主: Insect expression vector pBlueBacmsGCA1His (その他) 参照: UniProt: P63096 |
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#2: タンパク質 | 分子量: 37417.918 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNB1 発現宿主: Insect expression vector pBlueBacmsGCA1His (その他) 参照: UniProt: P62873 |
#3: タンパク質 | 分子量: 7859.173 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNG2 発現宿主: Insect expression vector pBlueBacmsGCA1His (その他) 参照: UniProt: P59768 |
-抗体 / タンパク質 / タンパク質・ペプチド / 非ポリマー , 4種, 5分子 NRL
#4: 抗体 | 分子量: 26236.244 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Mus musculus (ハツカネズミ) 発現宿主: Insect expression vector pBlueBacmsGCA1His (その他) |
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#5: タンパク質 | 分子量: 41406.410 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GHSR 発現宿主: Insect expression vector pBlueBacmsGCA1His (その他) 参照: UniProt: Q92847 |
#6: タンパク質・ペプチド | 分子量: 1471.657 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) Homo sapiens (ヒト) / 参照: UniProt: Q9UBU3 |
#7: 化合物 |
-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 | 名称: Complex of GHSR-Gi-ghrelin / タイプ: COMPLEX / Entity ID: #1-#6 / 由来: RECOMBINANT |
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分子量 | 実験値: NO |
由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Insect expression vector pBlueBacmsGCA1His (その他) |
緩衝液 | pH: 7.5 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 82 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3次元再構成 | 解像度: 2.7 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 280046 / 対称性のタイプ: POINT |