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- PDB-9mte: CryoEM structure of extracellular domain of human HER2 complexed ... -

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Basic information

Entry
Database: PDB / ID: 9mte
TitleCryoEM structure of extracellular domain of human HER2 complexed with two nano-bodies 27A05 and 47D05
Components
  • Receptor tyrosine-protein kinase erbB-2
  • VHH nanobody 27A05
  • VHH nanobody 47D05
KeywordsTRANSFERASE/IMMUNE SYSTEM / Nanobodies / VHH / Her2 / Complex / cancer / TRANSFERASE / TRANSFERASE-IMMUNE SYSTEM complex
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 / enzyme-linked receptor protein signaling pathway / ERBB2 Activates PTK6 Signaling / 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 / neuromuscular junction development / positive regulation of Rho protein signal transduction / positive regulation of MAP kinase activity / positive regulation of transcription by RNA polymerase I / ERBB2 Regulates Cell Motility / oligodendrocyte differentiation / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / regulation of angiogenesis / positive regulation of protein targeting to membrane / Schwann cell development / regulation of ERK1 and ERK2 cascade / 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 / SHC1 events in ERBB2 signaling / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Overexpressed ERBB2 / cell surface receptor protein tyrosine kinase signaling pathway / 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 / 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 / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / cellular response to growth factor stimulus / epidermal growth factor receptor signaling pathway / Downregulation of ERBB2 signaling / ruffle membrane / 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 / positive regulation of cell growth / RAF/MAP kinase cascade / presynaptic membrane / protein tyrosine kinase activity / basolateral plasma membrane / early endosome / protein phosphorylation / cell surface receptor signaling pathway / receptor complex / cell population proliferation / positive regulation of MAPK cascade / apical plasma membrane / endosome membrane / intracellular signal transduction / protein heterodimerization activity / signaling receptor binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / identical protein binding / membrane / nucleus / plasma membrane / cytosol
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 / 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
Similarity search - Component
Biological speciesLama glama (llama)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.66 Å
AuthorsBruch, E.M. / Rak, A.
Funding support France, 1items
OrganizationGrant numberCountry
Other private France
CitationJournal: Mol Cancer Ther / Year: 2026
Title: TPP-45142-an Anti-HER2 T cell Engager-Designed for Selective HER2-Low Cancer Immunotherapy.
Authors: Evelyn De Tavernier / Peter S Kim / Eduardo M Bruch / Virna F Cortez-Retamozo / Lien Timmerman / Alyssa L Flynn / Wouter Van Overbeke / Fabrice Tirode / Valeria Cintra Barbosa-Lorenzi / ...Authors: Evelyn De Tavernier / Peter S Kim / Eduardo M Bruch / Virna F Cortez-Retamozo / Lien Timmerman / Alyssa L Flynn / Wouter Van Overbeke / Fabrice Tirode / Valeria Cintra Barbosa-Lorenzi / Peter Piepenhagen / Thuvan Dinh-Le / Ernesto Luna / Aiqun Li / Ann Baker / Alexey Rak / Lily I Pao / Ana Paula B Vintém /
Abstract: The standard of care for patients with HER2-positive cancers is well established, but a significant unmet need exists for patients with HER2-low tumors, who do not meet the eligibility criteria for ...The standard of care for patients with HER2-positive cancers is well established, but a significant unmet need exists for patients with HER2-low tumors, who do not meet the eligibility criteria for trastuzumab, and for patients with HER2-positive tumors, who are refractory to trastuzumab treatment. Therefore, in this study, we developed a NANOBODY® domain-based HER2-targeting, T cell receptor (TCR)αβ-based T cell engager (TCE) molecule-TPP-45142; it recognizes a HER2 epitope distinct from that recognized by trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers such as breast, gastric, and gastroesophageal junction adenocarcinoma (GEJ) cancers. TPP-45142 mediated potent T cell-dependent cytotoxicity against HER2-low cancer cell lines in vitro and inhibited in vivo tumor growth of HER2-low breast cancer xenografts. TPP-45142 was highly selective toward tumor cells expressing low HER2 levels than toward normal cardiac cells and exhibited a favourable therapeutic index as per a cytokine release assay. Thus, TPP-45142, with an improved safety profile, is a promising next-generation TCE for treating challenging HER2-low cancers.
History
DepositionJan 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 19, 2025Provider: repository / Type: Initial release
Revision 1.0Nov 19, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 19, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.0Nov 19, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: VHH nanobody 27A05
B: VHH nanobody 47D05
C: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)99,4743
Polymers99,4743
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody VHH nanobody 27A05


Mass: 16135.509 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#2: Antibody VHH nanobody 47D05


Mass: 13917.577 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#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: 69420.812 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: CryoEM structure of extracellular domain of human HER2 complexed with two nano-bodies 27A05 and 47D05
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Lama glama (llama)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5 / Details: 50 mM Hepes pH7.5, 150 mM NaCl
SpecimenConc.: 1.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R0./1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: BF4 Bt4

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 20016

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
5cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.66 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2049675 / Symmetry type: POINT
RefinementHighest resolution: 2.66 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0025216
ELECTRON MICROSCOPYf_angle_d0.4477100
ELECTRON MICROSCOPYf_dihedral_angle_d3.906727
ELECTRON MICROSCOPYf_chiral_restr0.042810
ELECTRON MICROSCOPYf_plane_restr0.003919

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