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

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Basic information

Entry
Database: PDB / ID: 9t3s
TitleStructure of human HER2 in complex with EPS226 Fab
Components
  • EPS226 Fab HC
  • EPS226 Fab LC
  • Receptor tyrosine-protein kinase erbB-2
KeywordsANTITUMOR PROTEIN / Antibody Fab / Complex / cancer / extracellular domain.
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 / 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 / neurotransmitter receptor localization to postsynaptic specialization membrane / 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 / Signaling by ERBB2 / peptidyl-tyrosine phosphorylation / 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 / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to epidermal growth factor stimulus / basal plasma membrane / Constitutive Signaling by Overexpressed ERBB2 / Downregulation of ERBB2:ERBB3 signaling / 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 / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / 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 / signaling receptor complex / cell population proliferation / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsBirtley, J. / Regan, L. / Johnson, R.M. / Soni, K. / Pye, V.E. / Fitzgerald, K.
Funding support United Kingdom, 1items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 11, 2026Provider: repository / Type: Initial release
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Revision 1.0Mar 11, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Mar 11, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: EPS226 Fab HC
L: EPS226 Fab LC
A: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)121,6713
Polymers121,6713
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: Antibody EPS226 Fab HC


Mass: 28701.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody EPS226 Fab LC


Mass: 22719.027 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein Receptor tyrosine-protein kinase erbB-2 / 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: 70249.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB2, HER2, MLN19, NEU, NGL / Production host: Homo sapiens (human)
References: UniProt: P04626, 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: Human HER2 in complex with EPS232 Fab / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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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 defocus max: 1800 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: 4.39 sec. / Electron dose: 49.32 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 10400
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1Warp1.0.9particle selection
2EPU3.9image acquisition
4Warp1.0.9CTF correction
9PHENIX1.21.2_5419model refinement
10RELION5initial Euler assignment
11RELION5final Euler assignment
12RELION5classification
13RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1054132
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 309941 / Symmetry type: POINT
Atomic model buildingB value: 32.367
RefinementHighest resolution: 3 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035189
ELECTRON MICROSCOPYf_angle_d0.5377052
ELECTRON MICROSCOPYf_dihedral_angle_d5.115716
ELECTRON MICROSCOPYf_chiral_restr0.044796
ELECTRON MICROSCOPYf_plane_restr0.004912

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