登録情報 データベース : PDB / ID : 7mn5 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 要素(Receptor tyrosine-protein kinase erbB- ...) x 2 Isoform 6 of Pro-neuregulin-1, membrane-bound isoform 詳細キーワード SIGNALING PROTEIN / Complex / Receptor Tyrosine Kinase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 / 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 : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region ... : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Furin-like repeat / Furin-like repeats / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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 : 2.93 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) 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10月27日 Provider : repository / タイプ : Initial release改定 1.1 2021年11月10日 Group : Database references / カテゴリ : citation / citation_authorItem : _citation.country / _citation.journal_abbrev ... _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _citation_author.name 改定 1.2 2021年12月1日 Group : Database references / カテゴリ : citation / citation_authorItem : _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID改定 1.3 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