- EMDB-23917: The HER2 S310F/HER3/NRG1b Heterodimer -
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Basic information
Entry
Database: EMDB / ID: EMD-23917
Title
The HER2 S310F/HER3/NRG1b Heterodimer
Map data
Final HER2S310F/HER3/NRG1b ectodomain reconstruction at 3.1A resolution based on 0.143FSC metric. Filtered with the FSC and sharpened with b-factor of -90.
Sample
Complex: NRB1b-bound HER2-S310F/HER3 Heterodimer in the context of near full-length receptors
Complex: HER3
Protein or peptide: Receptor tyrosine-protein kinase erbB-3
Complex: HER2-S310F, MBP Fusion
Protein or peptide: Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-binding periplasmic protein
Complex: Neuregulin-1
Protein or peptide: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information
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 / Schwann cell development / negative regulation of signal transduction / 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 / myelination / Downregulation of ERBB2:ERBB3 signaling / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / 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 / basal plasma membrane / neurogenesis / regulation of ERK1 and ERK2 cascade / cell chemotaxis / positive regulation of translation / positive regulation of epithelial cell proliferation / 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 Similarity search - Function
: / 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 Similarity search - Domain/homology
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM139635
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
1F30CA247147
United States
German Research Foundation (DFG)
TR 1668/1-1
Germany
Citation
Journal: Nature / Year: 2021 Title: Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface. Authors: Devan Diwanji / Raphael Trenker / Tarjani M Thaker / Feng Wang / David A Agard / Kliment A Verba / Natalia Jura / Abstract: 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.
History
Deposition
Apr 30, 2021
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Header (metadata) release
Oct 27, 2021
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Map release
Oct 27, 2021
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Update
Dec 22, 2021
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Current status
Dec 22, 2021
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Download / File: emd_23917.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation
Final HER2S310F/HER3/NRG1b ectodomain reconstruction at 3.1A resolution based on 0.143FSC metric. Filtered with the FSC and sharpened with b-factor of -90.
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