+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-25763 | |||||||||
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タイトル | M22 Agonist Autoantibody bound to Human Thyrotropin receptor in complex with miniGs399 (composite structure) | |||||||||
マップデータ | Sharpened composite map | |||||||||
試料 |
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機能・相同性 | 機能・相同性情報 thyroid-stimulating hormone receptor activity / cochlea morphogenesis / inner ear receptor cell stereocilium organization / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / G protein-coupled peptide receptor activity / regulation of locomotion / PKA activation in glucagon signalling / hair follicle placode formation / lateral plasma membrane ...thyroid-stimulating hormone receptor activity / cochlea morphogenesis / inner ear receptor cell stereocilium organization / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / G protein-coupled peptide receptor activity / regulation of locomotion / PKA activation in glucagon signalling / hair follicle placode formation / lateral plasma membrane / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / hormone-mediated signaling pathway / adult locomotory behavior / B cell differentiation / trans-Golgi network membrane / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / bone development / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / cognition / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / platelet aggregation / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / basolateral plasma membrane / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.9 Å | |||||||||
データ登録者 | Faust B / Cheng Y / Manglik A | |||||||||
資金援助 | 2件
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引用 | ジャーナル: Nature / 年: 2022 タイトル: Autoantibody mimicry of hormone action at the thyrotropin receptor. 著者: Bryan Faust / Christian B Billesbølle / Carl-Mikael Suomivuori / Isha Singh / Kaihua Zhang / Nicholas Hoppe / Antonio F M Pinto / Jolene K Diedrich / Yagmur Muftuoglu / Mariusz W Szkudlinski ...著者: Bryan Faust / Christian B Billesbølle / Carl-Mikael Suomivuori / Isha Singh / Kaihua Zhang / Nicholas Hoppe / Antonio F M Pinto / Jolene K Diedrich / Yagmur Muftuoglu / Mariusz W Szkudlinski / Alan Saghatelian / Ron O Dror / Yifan Cheng / Aashish Manglik / 要旨: Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' ...Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity. How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves' disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G-protein-coupled receptors with large extracellular domains. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_25763.map.gz | 256.9 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-25763-v30.xml emd-25763.xml | 22.2 KB 22.2 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_25763.png | 110.4 KB | ||
その他 | emd_25763_additional_1.map.gz | 130.7 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-25763 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25763 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_25763_validation.pdf.gz | 446.7 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_25763_full_validation.pdf.gz | 446.3 KB | 表示 | |
XML形式データ | emd_25763_validation.xml.gz | 7.2 KB | 表示 | |
CIF形式データ | emd_25763_validation.cif.gz | 8.2 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25763 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25763 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_25763.map.gz / 形式: CCP4 / 大きさ: 278.6 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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注釈 | Sharpened composite map | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.844 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-追加マップ: Unsharpened composite map
ファイル | emd_25763_additional_1.map | ||||||||||||
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注釈 | Unsharpened composite map | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
+全体 : M22 agonist autoantibody bound to human Thyrotropin receptor in c...
+超分子 #1: M22 agonist autoantibody bound to human Thyrotropin receptor in c...
+分子 #1: M22 Fab light chain
+分子 #2: M22 Fab heavy chain
+分子 #3: Nanobody 35
+分子 #4: Thyrotropin receptor
+分子 #5: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+分子 #6: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+分子 #7: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+分子 #8: (2S)-3-hydroxypropane-1,2-diyl dihexadecanoate
+分子 #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 7.5 |
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グリッド | モデル: Quantifoil R1.2/1.3 / 材質: GOLD / メッシュ: 300 / 前処理 - タイプ: GLOW DISCHARGE |
凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | TFS KRIOS |
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特殊光学系 | エネルギーフィルター - 名称: GIF Bioquantum / エネルギーフィルター - スリット幅: 20 eV |
撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 60.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.0 µm / 最小 デフォーカス(公称値): 0.8 µm / 倍率(公称値): 81000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
+画像解析
-原子モデル構築 1
精密化 | プロトコル: FLEXIBLE FIT |
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得られたモデル | PDB-7t9n: |