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- EMDB-52998: HER2/ErbB2 extracellular domain (ECD) in extended conformation in... -

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Entry
Database: EMDB / ID: EMD-52998
TitleHER2/ErbB2 extracellular domain (ECD) in extended conformation in complex with trastuzumab (TZB) antibody
Map dataFull map from refinement, used for modelling.
Sample
  • Complex: Ternary complex of HER2/ErbB2 in its canonical conformation with trastuzumab (TZB) antibody.
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein
KeywordsReceptor / tyrosine kinase / transmembrane / HER2 / SIGNALING PROTEIN
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 / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse ...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 / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse / regulation of microtubule-based process / 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 / 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 / positive regulation of cell adhesion / GRB2 events in ERBB2 signaling / Downregulation of ERBB2:ERBB3 signaling / SHC1 events in ERBB2 signaling / cell surface receptor protein tyrosine kinase signaling pathway / basal plasma membrane / peptidyl-tyrosine phosphorylation / cellular response to epidermal growth factor stimulus / Constitutive Signaling by Overexpressed ERBB2 / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsGragera M / Buschiazzo A / Vacca S
Funding supportEuropean Union, 1 items
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, 2025-
Header (metadata) releaseAug 6, 2025-
Map releaseAug 6, 2025-
UpdateAug 6, 2025-
Current statusAug 6, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52998.png

Downloads & links

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Map

FileDownload / File: emd_52998.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map from refinement, used for modelling.
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 200 pix.
= 260.4 Å		1.3 Å/pix.
x 200 pix.
= 260.4 Å		1.3 Å/pix.
x 200 pix.
= 260.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.302 Å
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Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-0.60871375 - 1.644241
Average (Standard dev.)-0.00008193596 (±0.04483844)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 260.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52998_msk_1.map
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Additional map: Sharpened map with deepEMhancer from the refined map.

Fileemd_52998_additional_1.map
AnnotationSharpened map with deepEMhancer from the refined map.
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Additional map: Sharpened map with relion post-processing from the refined map.

Fileemd_52998_additional_2.map
AnnotationSharpened map with relion post-processing from the refined map.
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Additional map: Full map of the unmasked refinement

Fileemd_52998_additional_3.map
AnnotationFull map of the unmasked refinement
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Additional map: Half map of the unmasked refinement

Fileemd_52998_additional_4.map
AnnotationHalf map of the unmasked refinement
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Additional map: Half map of the unmasked refinement

Fileemd_52998_additional_5.map
AnnotationHalf map of the unmasked refinement
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Half map: #1

Fileemd_52998_half_map_1.map
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Half map: #2

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Sample components

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Entire : Ternary complex of HER2/ErbB2 in its canonical conformation with ...

EntireName: Ternary complex of HER2/ErbB2 in its canonical conformation with trastuzumab (TZB) antibody.
Components
  • Complex: Ternary complex of HER2/ErbB2 in its canonical conformation with trastuzumab (TZB) antibody.
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein

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Supramolecule #1: Ternary complex of HER2/ErbB2 in its canonical conformation with ...

SupramoleculeName: Ternary complex of HER2/ErbB2 in its canonical conformation with trastuzumab (TZB) antibody.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD.
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 112 KDa

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Macromolecule #1: Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2,Green fluorescent protein
type: protein_or_peptide / ID: 1
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 (from residues S22 to E542). ...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 (from residues S22 to E542).,Near-full length HER2/ErbB2 in complex with full length humanized monoclonal antibody trastuzumab (TZB). The final reconstruction contains only the HER2 ECD head (from residues S22 to E542).
Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Aequorea victoria (jellyfish)
Molecular weightTheoretical: 146.753172 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKFLVNVALV FMVVYISYIY ADYKDDDDKH HHHHHHHHHL EVLFQGPYPY DVPDYSTQVC TGTDMKLRLP ASPETHLDML RHLYQGCQV VQGNLELTYL PTNASLSFLQ DIQEVQGYVL IAHNQVRQVP LQRLRIVRGT QLFEDNYALA VLDNGDPLNN T TPVTGASP ...String:
MKFLVNVALV FMVVYISYIY ADYKDDDDKH HHHHHHHHHL EVLFQGPYPY DVPDYSTQVC TGTDMKLRLP ASPETHLDML RHLYQGCQV VQGNLELTYL PTNASLSFLQ DIQEVQGYVL IAHNQVRQVP LQRLRIVRGT QLFEDNYALA VLDNGDPLNN T TPVTGASP GGLRELQLRS LTEILKGGVL IQRNPQLCYQ DTILWKDIFH KNNQLALTLI DTNRSRACHP CSPMCKGSRC WG ESSEDCQ SLTRTVCAGG CARCKGPLPT DCCHEQCAAG CTGPKHSDCL ACLHFNHSGI CELHCPALVT YNTDTFESMP NPE GRYTFG ASCVTACPYN YLSTDVGSCT LVCPLHNQEV TAEDGTQRCE KCSKPCARVC YGLGMEHLRE VRAVTSANIQ EFAG CKKIF GSLAFLPESF DGDPASNTAP LQPEQLQVFE TLEEITGYLY ISAWPDSLPD LSVFQNLQVI RGRILHNGAY SLTLQ GLGI SWLGLRSLRE LGSGLALIHH NTHLCFVHTV PWDQLFRNPH QALLHTANRP EDECVGEGLA CHQLCARGHC WGPGPT QCV NCSQFLRGQE CVEECRVLQG LPREYVNARH CLPCHPECQP QNGSVTCFGP EADQCVACAH YKDPPFCVAR CPSGVKP DL SYMPIWKFPD EEGACQPCPI NCTHSCVDLD DKGCPAEQRA SPLTSIISAV VGILLVVVLG VVFGILIKRR QQKIRKYT M RRLLQETELV EPLTPSGAMP NQAQMRILKE TELRKVKVLG SGAFGTVYKG IWIPDGENVK IPVAIKVLRE NTSPKANKE ILDEAYVMAG VGSPYVSRLL GISLTSTVQL VTQLMPYGSL LDHVRENRGR LGSQDLLNWC MQIAKGMSYL EDVRLVHRDL AARNVLVKS PNHVKITDFG LARLLDIDET EYHADGGKVP IKWMALESIL RRRFTHQSDV WSYGVTVWEL MTFGAKPYDG I PAREIPDL LEKGERLPQP PICTIDVYMI MVKCWMIDSE SRPRFRELVS EFSRMARDPQ RFVVIQNEDL GPASPLDSTF YR SLLEDDD MGDLVDAEEY LVPQQGLEVL FQGPGSMSKG EELFTGVVPI LVELDGDVNG HKFSVRGEGE GDATNGKLTL KFI CTTGKL PVPWPTLVTT LTYGVQCFSR YPDHMKRHDF FKSAMPEGYV QERTISFKDD GTYKTRAEVK FEGDTLVNRI ELKG IDFKE DGNILGHKLE YNFNSHNVYI TADKQKNGIK ANFKIRHNVE DGSVQLADHY QQNTPIGDGP VLLPDNHYLS TQSVL SKDP NEKRDHMVLL EFVTAAGITH GMDELYK

UniProtKB: Receptor tyrosine-protein kinase erbB-2, Green fluorescent protein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
SoftwareName: EPU
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 2 / Number real images: 24624 / Average exposure time: 1.2 sec. / Average electron dose: 72.3 e/Å2
Details: Two grids imaged: - Grid 1: 5428 movies. - Grid 2: 19196 movies.
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4207722
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
In silico model: Ab-initio reconstruction from experimental particles using cryoSPARC v3.2
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 77784
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4) / Details: CryoSPARC v4.4
Final 3D classificationNumber classes: 4 / Software: (Name: cryoSPARC, Xmipp)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

5my6


Chain - Source name: PDB / Chain - Initial model type: experimental model
SoftwareName: UCSF Chimera
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Target criteria: Cross-correlation coefficient
Output model

PDB-9qbg:
HER2/ErbB2 extracellular domain (ECD) in extended conformation in complex with trastuzumab (TZB) antibody

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