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- PDB-9qbf: HER2/ErbB2 extracellular domain (ECD) in compact conformation in ... -

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基本情報

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データベース: PDB / ID: 9qbf
タイトルHER2/ErbB2 extracellular domain (ECD) in compact conformation in complex with trastuzumab (TZB) antibody
要素Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein
キーワードSIGNALING PROTEIN / Receptor / tyrosine kinase / transmembrane / HER2
機能・相同性
機能・相同性情報


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 / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance ...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 / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2 Activates PTK6 Signaling / enzyme-linked receptor protein signaling pathway / neuromuscular junction development / ERBB2-ERBB3 signaling pathway / positive regulation of Rho protein signal transduction / 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 / positive regulation of transcription by RNA polymerase I / positive regulation of MAP kinase activity / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / oligodendrocyte differentiation / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / Schwann cell development / Downregulation of ERBB2:ERBB3 signaling / coreceptor activity / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / transmembrane receptor protein tyrosine kinase activity / GRB2 events in ERBB2 signaling / positive regulation of cell adhesion / SHC1 events in ERBB2 signaling / basal plasma membrane / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / cellular response to epidermal growth factor stimulus / bioluminescence / peptidyl-tyrosine phosphorylation / positive regulation of translation / positive regulation of epithelial cell proliferation / generation of precursor metabolites and energy / neuromuscular junction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / Signaling by ERBB2 TMD/JMD mutants / Downregulation of ERBB2 signaling / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / cellular response to growth factor stimulus / ruffle membrane / epidermal growth factor receptor signaling pathway / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / heart development / presynaptic membrane / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / early endosome / cell surface receptor signaling pathway / endosome membrane / cell population proliferation / protein phosphorylation / receptor complex / positive regulation of MAPK cascade / intracellular signal transduction / apical plasma membrane / protein heterodimerization activity / signaling receptor binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane
類似検索 - 分子機能
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Growth factor receptor cysteine-rich domain superfamily / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
類似検索 - ドメイン・相同性
Receptor tyrosine-protein kinase erbB-2 / Green fluorescent protein
類似検索 - 構成要素
生物種Homo sapiens (ヒト)
Aequorea victoria (オワンクラゲ)
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: 3.8 Å
データ登録者Gragera, M. / Buschiazzo, A. / Vacca, S.
資金援助European Union, 1件
組織認可番号国
European Research Council (ERC)HighResCells (ERC-2018-SyG, Proposal 810057)European Union
引用ジャーナル: Sci Adv / 年: 2025
タイトル: Structural analysis of HER2-trastuzumab complex reveals receptor conformational adaptation.
著者: Santiago Vacca / Marcos Gragera / Alejandro Buschiazzo / David Herreros / James M Krieger / Santiago Bonn-Garcia / Roberto Melero / Carlos Os Sorzano / Jose M Carazo / Ohad Medalia / Andreas Plückthun /
要旨: Human epidermal growth factor receptor-2 (HER2) is a receptor tyrosine kinase, associated with a variety of malignant tumors, usually through overexpression, resulting in aberrant signaling. ...Human epidermal growth factor receptor-2 (HER2) is a receptor tyrosine kinase, associated with a variety of malignant tumors, usually through overexpression, resulting in aberrant signaling. Trastuzumab (TZB), one of the monoclonal antibodies (mAbs) used in combination with chemotherapy, has become a major therapeutic for HER2-overexpressing cancers. Current structural understanding of HER2 and its interactions with other receptors and with different affinity agents has relied on numerous structures of individual domains of HER2. Here, we subjected purified near full-length HER2 to single-particle cryo-electron microscopy (cryo-EM) analysis. Besides the canonical conformation described in previous structural studies, we report a previously unreported conformation of the HER2 extracellular domain that is stabilized upon TZB binding, which might hamper association with HER3, a receptor with which HER2 forms an oncogenic unit. Together, our findings provide insights into the conformational dynamics of the HER2 receptor and the mechanism of action of TZB.
履歴
登録2025年3月2日登録サイト: PDBE / 処理サイト: PDBE
改定 1.02025年8月6日Provider: repository / タイプ: Initial release

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構造の表示

構造ビューア分子:
MolmilJmol/JSmol

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集合体

登録構造単位
A: Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein


分子量 (理論値)分子数
合計 (水以外)146,7371
ポリマ－146,7371
非ポリマー00
水00
1


  • 登録構造と同一
  • 登録者・ソフトウェアが定義した集合体
  • 根拠: 電子顕微鏡法, not applicable
タイプ名称対称操作数
identity operation1_555x,y,z1

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要素

#1: タンパク質 Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein / Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / ...Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / Tyrosine kinase-type cell surface receptor HER2 / p185erbB2


分子量: 146737.172 Da / 分子数: 1 / 変異: Del1-22,Del1030-1255,C789S,C805S,C965S. / 由来タイプ: 組換発現
詳細: Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 ...詳細: Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head.
由来: (組換発現) Homo sapiens (ヒト), (組換発現) Aequorea victoria (オワンクラゲ)
遺伝子: ERBB2, HER2, MLN19, NEU, NGL, GFP / 細胞株 (発現宿主): Sf9
発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ)
参照: UniProt: P04626, UniProt: P42212, receptor protein-tyrosine kinase
Has protein modificationY

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実験情報

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実験

実験手法: 電子顕微鏡法
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

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試料調製

構成要素名称: Ternary complex of HER2/ErbB2 in compact conformation with trastuzumab (TZB) antibody.
タイプ: COMPLEX
詳細: Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD.
Entity ID: all / 由来: RECOMBINANT
分子量
IDEntity assembly-ID値 (°)実験値
110.148 MDaNO
210.148 MDaNO
310.112 MDaNO
由来(天然)生物種: Homo sapiens (ヒト)
由来(組換発現)生物種: Spodoptera frugiperda (ツマジロクサヨトウ)
細胞: Sf9
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
試料支持グリッドの材料: GOLD / グリッドのサイズ: 200 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3
急速凍結装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 277.15 K

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電子顕微鏡撮影

実験機器
モデル: Titan Krios / 画像提供: FEI Company
顕微鏡モデル: TFS 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 / 倍率（公称値）: 130000 X / 最大 デフォーカス（公称値）: 2400 nm / 最小 デフォーカス（公称値）: 800 nm / Cs: 2.7 mm
試料ホルダ凍結剤: NITROGEN
試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER
撮影平均露光時間: 1.2 sec. / 電子線照射量: 72.3 e/Å2
フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k)
撮影したグリッド数: 2 / 実像数: 24624
詳細: Two grids imaged: - Grid 1: 5428 movies. - Grid 2: 19196 movies.
電子光学装置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

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解析

EMソフトウェア
ID名称バージョンカテゴリ
10cryoSPARC4.4最終オイラー角割当
13Coot0.9.6モデル精密化
14PHENIX1.21.1_5286:モデル精密化
15RosettaEM2024.09+release.06b3cf8ad0モデル精密化
CTF補正タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION
粒子像の選択選択した粒子像数: 4207722
対称性点対称性: C1 (非対称)
3次元再構成解像度: 3.8 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 91370 / 対称性のタイプ: POINT
原子モデル構築プロトコル: RIGID BODY FIT / 空間: REAL / Target criteria: Cross-correlation coefficient
原子モデル構築PDB-ID: 5MY6

5my6


Accession code: 5MY6 / Source name: PDB / タイプ: experimental model

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