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- EMDB-55518: Structure of human HER2 in complex with EPS226 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-55518
TitleStructure of human HER2 in complex with EPS226 Fab
Map dataFinal sharpened map for HER2 bound to EPS226 Fab
Sample
  • Complex: Human HER2 in complex with EPS232 Fab
    • Protein or peptide: EPS226 Fab HC
    • Protein or peptide: EPS226 Fab LC
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
KeywordsAntibody Fab / Complex / cancer / extracellular domain. / ANTITUMOR PROTEIN
Function / homology
Function and homology information


negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / immature T cell proliferation in thymus / GRB7 events in ERBB2 signaling / RNA polymerase I core binding / semaphorin receptor complex / Developmental Lineage of Mammary Stem Cells / 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 / immature T cell proliferation in thymus / GRB7 events in ERBB2 signaling / RNA polymerase I core binding / semaphorin receptor complex / Developmental Lineage of Mammary Stem Cells / 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 / enzyme-linked receptor protein signaling pathway / ERBB2 Activates PTK6 Signaling / ERBB2-EGFR signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / 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 Rho protein signal transduction / neuromuscular junction development / positive regulation of transcription by RNA polymerase I / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / oligodendrocyte differentiation / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / regulation of angiogenesis / positive regulation of protein targeting to membrane / regulation of ERK1 and ERK2 cascade / Schwann cell development / coreceptor activity / peptidyl-tyrosine phosphorylation / 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 / SHC1 events in ERBB2 signaling / positive regulation of cell adhesion / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / Downregulation of ERBB2:ERBB3 signaling / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of epithelial cell proliferation / positive regulation of translation / neuromuscular junction / wound healing / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by ERBB2 TMD/JMD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Downregulation of ERBB2 signaling / ruffle membrane / epidermal growth factor receptor signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / neuron differentiation / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / presynaptic membrane / basolateral plasma membrane / protein phosphorylation / early endosome / positive regulation of MAPK cascade / cell surface receptor signaling pathway / cell population proliferation / signaling receptor complex / endosome membrane / apical plasma membrane / intracellular signal transduction / protein heterodimerization activity / signaling receptor binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / membrane / identical protein binding / nucleus
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 / 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
Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsBirtley J / Regan L / Johnson RM / Soni K / Pye VE / Fitzgerald K
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Not funded United Kingdom
CitationJournal: Sci Rep / Year: 2026
Title: Elucidating the relationship between affinity and potency in the performance of therapeutic IgE.
Authors: Francesca Marano / Callum McKenzie / James R Birtley / Sadaf A Hussain / Olivia Macleod / Alexander Goodacre / Shuang Wu / Oliver E Amin / Nikhil Faulkner / John Devlin / Liam Regan / Komal ...Authors: Francesca Marano / Callum McKenzie / James R Birtley / Sadaf A Hussain / Olivia Macleod / Alexander Goodacre / Shuang Wu / Oliver E Amin / Nikhil Faulkner / John Devlin / Liam Regan / Komal Soni / Rachel M Johnson / Valerie E Pye / Tim Wilson / Elizabeth Hardaker / Kevin FitzGerald /
Abstract: IgE antibodies exert strong immunostimulatory effects and their anti-tumour effectiveness is currently being assessed in clinical trials. The high affinity of IgE for FcεRI may result in the binding ...IgE antibodies exert strong immunostimulatory effects and their anti-tumour effectiveness is currently being assessed in clinical trials. The high affinity of IgE for FcεRI may result in the binding of exogenously delivered antibody to effector cells prior to antigen engagement, potentially leading to IgE being presented multivalently to cancer cells. With the presumed higher avidity of antigen binding it is unclear whether increasing monovalent affinity of IgE improves anti-tumour functionality. To address this, we affinity-matured an anti-HER2 IgE, generating 12 clones with increased affinity for HER2. These clones were more potent than the parental antibody in inducing mast cell degranulation, with the most potent, EPS 232, achieving enhanced antibody-dependent cytotoxicity and phagocytosis of HER2-expressing cancer cells. EPS 232 delivered superior tumour growth inhibition in vivo, including in models expressing ultra-low levels of HER2, and it promoted greater infiltration of T cells and macrophages into tumours. These findings suggest that for therapeutic IgE, increasing antigen-binding affinity can lead to functional enhancements.
History
DepositionOct 29, 2025-
Header (metadata) releaseMar 11, 2026-
Map releaseMar 11, 2026-
UpdateApr 15, 2026-
Current statusApr 15, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_55518.png

Downloads & links

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Map

FileDownload / File: emd_55518.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFinal sharpened map for HER2 bound to EPS226 Fab
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 360 pix.
= 262.44 Å		0.73 Å/pix.
x 360 pix.
= 262.44 Å		0.73 Å/pix.
x 360 pix.
= 262.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.729 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.02379623 - 0.04564573
Average (Standard dev.)0.00003880058 (±0.0006393103)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 262.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_55518_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Final unsharpened map for HER2 bound to EPS226 Fab

Fileemd_55518_additional_1.map
AnnotationFinal unsharpened map for HER2 bound to EPS226 Fab
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_55518_half_map_1.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_55518_half_map_2.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human HER2 in complex with EPS232 Fab

EntireName: Human HER2 in complex with EPS232 Fab
Components
  • Complex: Human HER2 in complex with EPS232 Fab
    • Protein or peptide: EPS226 Fab HC
    • Protein or peptide: EPS226 Fab LC
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2

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Supramolecule #1: Human HER2 in complex with EPS232 Fab

SupramoleculeName: Human HER2 in complex with EPS232 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: EPS226 Fab HC

MacromoleculeName: EPS226 Fab HC / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.701863 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYAMHWVRQA PGQRLEWIGW INAGNGNTKY SQKFQGRVTI TRDTSASTAY MELSSLRSE DTAVYYCARD FSSQVATAAV DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYAMHWVRQA PGQRLEWIGW INAGNGNTKY SQKFQGRVTI TRDTSASTAY MELSSLRSE DTAVYYCARD FSSQVATAAV DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTS GQAGQHHHHH HG AEQKLIS EEDLGGLNDI FEAQKIEWHE

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Macromolecule #2: EPS226 Fab LC

MacromoleculeName: EPS226 Fab LC / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.719027 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVLTQPASV SGSPGQSITI SCTGTSSDVG SYNLVSWYQQ HPGKAPKLMI YEVSNRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYY CSSYTSSSTL VFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP ...String:
QSVLTQPASV SGSPGQSITI SCTGTSSDVG SYNLVSWYQQ HPGKAPKLMI YEVSNRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYY CSSYTSSSTL VFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP SKQSNNKYAA SSYLSLTPEQ WKSHRSYSCQ VTHEGSTVEK TVAPTECS

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Macromolecule #3: Receptor tyrosine-protein kinase erbB-2

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.249711 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: TQVCTGTDMK LRLPASPETH LDMLRHLYQG CQVVQGNLEL TYLPTNASLS FLQDIQEVQG YVLIAHNQVR QVPLQRLRIV RGTQLFEDN YALAVLDNGD PLNNTTPVTG ASPGGLRELQ LRSLTEILKG GVLIQRNPQL CYQDTILWKD IFHKNNQLAL T LIDTNRSR ...String:
TQVCTGTDMK LRLPASPETH LDMLRHLYQG CQVVQGNLEL TYLPTNASLS FLQDIQEVQG YVLIAHNQVR QVPLQRLRIV RGTQLFEDN YALAVLDNGD PLNNTTPVTG ASPGGLRELQ LRSLTEILKG GVLIQRNPQL CYQDTILWKD IFHKNNQLAL T LIDTNRSR ACHPCSPMCK GSRCWGESSE DCQSLTRTVC AGGCARCKGP LPTDCCHEQC AAGCTGPKHS DCLACLHFNH SG ICELHCP ALVTYNTDTF ESMPNPEGRY TFGASCVTAC PYNYLSTDVG SCTLVCPLHN QEVTAEDGTQ RCEKCSKPCA RVC YGLGME HLREVRAVTS ANIQEFAGCK KIFGSLAFLP ESFDGDPASN TAPLQPEQLQ VFETLEEITG YLYISAWPDS LPDL SVFQN LQVIRGRILH NGAYSLTLQG LGISWLGLRS LRELGSGLAL IHHNTHLCFV HTVPWDQLFR NPHQALLHTA NRPED ECVG EGLACHQLCA RGHCWGPGPT QCVNCSQFLR GQECVEECRV LQGLPREYVN ARHCLPCHPE CQPQNGSVTC FGPEAD QCV ACAHYKDPPF CVARCPSGVK PDLSYMPIWK FPDEEGACQP CPINCTHSCV DLDDKGCPAE QRASPLTHHH HHH

UniProtKB: Receptor tyrosine-protein kinase erbB-2

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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

Concentration0.1 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 10400 / Average exposure time: 4.39 sec. / Average electron dose: 49.32 e/Å2
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: 1.8 µm / Nominal defocus min: 0.8 µm
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: 1054132
CTF correctionSoftware - Name: Warp (ver. 1.0.9) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 309941
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final 3D classificationSoftware - Name: RELION (ver. 5.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementOverall B value: 32.367
Output model

PDB-9t3s:
Structure of human HER2 in complex with EPS226 Fab

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