登録情報 データベース : PDB / ID : 7mn8 構造の表示 ダウンロードとリンクタイトル Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain bound to Trastuzumab Fab 要素(Receptor tyrosine-protein kinase erbB- ...) x 2 (Trastuzumab Fab ...) x 2 Isoform 6 of Pro-neuregulin-1, membrane-bound isoform 詳細キーワード SIGNALING PROTEIN/IMMUNE SYSTEM / Complex / Receptor Tyrosine Kinase / Herceptin / Trastuzumab / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
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 / PLCG1 events in ERBB2 signaling ... 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 / PLCG1 events in ERBB2 signaling / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / semaphorin receptor complex / protein tyrosine kinase activator activity / positive regulation of calcineurin-NFAT signaling cascade / peripheral nervous system development / Signaling by ERBB4 / regulation of microtubule-based process / ErbB-3 class receptor binding / negative regulation of cell adhesion / negative regulation of motor neuron apoptotic process / ERBB2 Regulates Cell Motility / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / PI3K events in ERBB2 signaling / motor neuron apoptotic process / neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of Rho protein signal transduction / neuromuscular junction development / 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 / detection of maltose stimulus / enzyme-linked receptor protein signaling pathway / maltose transport complex / ERBB2-ERBB3 signaling pathway / positive regulation of transcription by RNA polymerase I / oligodendrocyte differentiation / growth factor binding / carbohydrate transport / semaphorin-plexin signaling pathway / cellular response to epidermal growth factor stimulus / Signaling by ERBB2 / 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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / regulation of angiogenesis / neurogenesis / SHC1 events in ERBB2 signaling / coreceptor activity / negative regulation of signal transduction / regulation of ERK1 and ERK2 cascade / Schwann cell development / basal plasma membrane / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / positive regulation of epithelial cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / cell surface receptor protein tyrosine kinase signaling pathway / myelination / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Downregulation of ERBB2:ERBB3 signaling / ATP-binding cassette (ABC) transporter complex / Constitutive Signaling by Overexpressed ERBB2 / cell chemotaxis / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of translation / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / ruffle membrane / wound healing / neuromuscular junction / peptidyl-tyrosine phosphorylation / neuron differentiation / transmembrane signaling receptor activity / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / myelin sheath 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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding 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 / Maltose/maltodextrin-binding periplasmic protein / Receptor tyrosine-protein kinase erbB-3 / Isoform 6 of Pro-neuregulin-1, membrane-bound isoform 類似検索 - 構成要素生物種 Homo sapiens (ヒト)Escherichia coli (大腸菌)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 : 3.45 Å 詳細データ登録者 Diwanji, D. / Trenker, R. / Verba, K.A. / Jura, N. 資金援助 米国, ドイツ, 3件 詳細 詳細を隠す組織 認可番号 国 National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) GM139635 米国 National Institutes of Health/National Cancer Institute (NIH/NCI) 1F30CA247147 米国 German Research Foundation (DFG) TR 1668/1-1 ドイツ
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 登録 2021年4月30日 登録サイト : RCSB / 処理サイト : RCSB改定 1.0 2021年11月10日 Provider : repository / タイプ : Initial release改定 1.1 2021年12月1日 Group : Database references / Source and taxonomy / カテゴリ : citation / citation_author / entity_src_genItem : _citation.pdbx_database_id_PubMed / _citation.title ... _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _entity_src_gen.pdbx_gene_src_scientific_name 改定 1.2 2021年12月22日 Group : Database references / カテゴリ : citation / citation_authorItem : _citation.journal_volume / _citation.page_first ... _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
すべて表示 表示を減らす