+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-23918 | ||||||||||||
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タイトル | Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain bound to Trastuzumab Fab | ||||||||||||
マップデータ | Main map from non-uniform refinement in cryosparc, filtered to 3.45A in resolution and sharpened with a B-factor of 100.3 | ||||||||||||
試料 |
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機能・相同性 | 機能・相同性情報 neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway ...neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / positive regulation of calcineurin-NFAT signaling cascade / peripheral nervous system development / regulation of microtubule-based process / ErbB-3 class receptor binding / negative regulation of cell adhesion / negative regulation of motor neuron apoptotic process / semaphorin receptor complex / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / motor neuron apoptotic process / PLCG1 events in ERBB2 signaling / neuromuscular junction development / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / positive regulation of Rho protein signal transduction / detection of maltose stimulus / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / enzyme-linked receptor protein signaling pathway / positive regulation of transcription by RNA polymerase I / maltose transport complex / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / Signaling by ERBB4 / oligodendrocyte differentiation / growth factor binding / carbohydrate transport / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / carbohydrate transmembrane transporter activity / positive regulation of cell adhesion / maltose binding / lateral plasma membrane / maltose transport / maltodextrin transmembrane transport / positive regulation of protein targeting to membrane / regulation of angiogenesis / coreceptor activity / negative regulation of signal transduction / Schwann cell development / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / extrinsic apoptotic signaling pathway in absence of ligand / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cell surface receptor protein tyrosine kinase signaling pathway / GRB2 events in ERBB2 signaling / myelination / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Downregulation of ERBB2:ERBB3 signaling / transmembrane receptor protein tyrosine kinase activity / ATP-binding cassette (ABC) transporter complex / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / phosphatidylinositol 3-kinase/protein kinase B signal transduction / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / cell chemotaxis / positive regulation of epithelial cell proliferation / positive regulation of translation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / neuromuscular junction / neuron differentiation / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Downregulation of ERBB2 signaling / ruffle membrane / peptidyl-tyrosine phosphorylation / transmembrane signaling receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / myelin sheath 類似検索 - 分子機能 | ||||||||||||
生物種 | Homo sapiens (ヒト) / Escherichia coli (大腸菌) | ||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.45 Å | ||||||||||||
データ登録者 | Diwanji D / Trenker R / Verba KA / Jura N | ||||||||||||
資金援助 | 米国, ドイツ, 3件
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引用 | ジャーナル: Nature / 年: 2021 タイトル: Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface. 著者: Devan Diwanji / Raphael Trenker / Tarjani M Thaker / Feng Wang / David A Agard / Kliment A Verba / Natalia Jura / 要旨: Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact ...Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1β-bound near full-length HER2-HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellulardomain module, revealing unexpected dynamics at the HER2-HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. Both HER2-HER3 and HER2(S310F)-HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. Our structure of the HER2(S310F)-HER3-NRG1β-trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2-HER3 heterodimer. The unique features of a singly liganded HER2-HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface. | ||||||||||||
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 | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_23918.map.gz | 307 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-23918-v30.xml emd-23918.xml | 26.3 KB 26.3 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_23918_fsc.xml | 15.4 KB | 表示 | FSCデータファイル |
画像 | emd_23918.png | 176.4 KB | ||
マスクデータ | emd_23918_msk_1.map | 325 MB | マスクマップ | |
その他 | emd_23918_half_map_1.map.gz emd_23918_half_map_2.map.gz | 301.4 MB 301.4 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-23918 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23918 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_23918_validation.pdf.gz | 189.1 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_23918_full_validation.pdf.gz | 188.7 KB | 表示 | |
XML形式データ | emd_23918_validation.xml.gz | 503 B | 表示 | |
CIF形式データ | emd_23918_validation.cif.gz | 373 B | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23918 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23918 | 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_23918.map.gz / 形式: CCP4 / 大きさ: 325 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | Main map from non-uniform refinement in cryosparc, filtered to 3.45A in resolution and sharpened with a B-factor of 100.3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.834 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-マスク #1
ファイル | emd_23918_msk_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: EM Half-map A
ファイル | emd_23918_half_map_1.map | ||||||||||||
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注釈 | EM Half-map A | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: EM Half-map B
ファイル | emd_23918_half_map_2.map | ||||||||||||
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注釈 | EM Half-map B | ||||||||||||
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 : NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in...
+超分子 #1: NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in...
+超分子 #2: Trastuzumab (Herceptin) Fab
+超分子 #3: Neuregulin-1b isoform 6
+超分子 #4: HER3
+超分子 #5: HER2-S310F-MBP Fusion
+分子 #1: Receptor tyrosine-protein kinase erbB-3
+分子 #2: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
+分子 #3: Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-bind...
+分子 #4: Trastuzumab Fab Light Chain
+分子 #5: Trastuzumab Fab Heavy Chain
+分子 #8: 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: 7.4 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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特殊光学系 | 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: 66.0 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 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |