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

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Entry
Database: PDB / ID: 9qbf
TitleHER2/ErbB2 extracellular domain (ECD) in compact conformation in complex with trastuzumab (TZB) antibody
ComponentsReceptor tyrosine-protein kinase erbB-2,Green fluorescent protein
KeywordsSIGNALING PROTEIN / Receptor / tyrosine kinase / transmembrane / HER2
Function / homology
Function and homology information


negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / RNA polymerase I core binding / immature T cell proliferation in thymus / 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 / RNA polymerase I core binding / immature T cell proliferation in thymus / 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 / ERBB2 Activates PTK6 Signaling / neurotransmitter receptor localization to postsynaptic specialization membrane / enzyme-linked receptor protein signaling pathway / neuromuscular junction development / positive regulation of Rho protein signal transduction / ERBB2-ERBB3 signaling pathway / 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 MAP kinase activity / positive regulation of transcription by RNA polymerase I / 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 / 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 / Downregulation of ERBB2:ERBB3 signaling / cell surface receptor protein tyrosine kinase signaling pathway / basal plasma membrane / Constitutive Signaling by Overexpressed ERBB2 / cellular response to epidermal growth factor stimulus / peptidyl-tyrosine phosphorylation / bioluminescence / 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 / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / receptor tyrosine kinase binding / Signaling by ERBB2 KD Mutants / cellular response to growth factor stimulus / ruffle membrane / Downregulation of ERBB2 signaling / 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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / early endosome / cell surface receptor signaling pathway / cell population proliferation / protein phosphorylation / receptor complex / endosome membrane / 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
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 / 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
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2 / Green fluorescent protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Aequorea victoria (jellyfish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsGragera, M. / Buschiazzo, A. / Vacca, S.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Research Council (ERC)HighResCells (ERC-2018-SyG, Proposal 810057)European Union
CitationJournal: Sci Adv / Year: 2025
Title: Structural analysis of HER2-trastuzumab complex reveals receptor conformational adaptation.
Authors: 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 /
Abstract: 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.
History
DepositionMar 2, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 6, 2025Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein


Theoretical massNumber of molelcules
Total (without water)146,7371
Polymers146,7371
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein 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


Mass: 146737.172 Da / Num. of mol.: 1 / Mutation: Del1-22,Del1030-1255,C789S,C805S,C965S.
Source method: isolated from a genetically manipulated source
Details: 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 ...Details: 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.
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Aequorea victoria (jellyfish)
Gene: ERBB2, HER2, MLN19, NEU, NGL, GFP / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04626, UniProt: P42212, receptor protein-tyrosine kinase
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Ternary complex of HER2/ErbB2 in compact conformation with trastuzumab (TZB) antibody.
Type: COMPLEX
Details: 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 / Source: RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.148 MDaNO
210.148 MDaNO
310.112 MDaNO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.2 sec. / Electron dose: 72.3 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 24624
Details: Two grids imaged: - Grid 1: 5428 movies. - Grid 2: 19196 movies.
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
10cryoSPARC4.4final Euler assignment
13Coot0.9.6model refinement
14PHENIX1.21.1_5286:model refinement
15RosettaEM2024.09+release.06b3cf8ad0model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4207722
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 91370 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL / Target criteria: Cross-correlation coefficient
Atomic model buildingPDB-ID: 5MY6

5my6


Accession code: 5MY6 / Source name: PDB / Type: experimental model

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