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- EMDB-68255: The structure of HER2-m66-trastuzumab -

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Basic information

Entry
Database: EMDB / ID: EMD-68255
TitleThe structure of HER2-m66-trastuzumab
Map dataNone
Sample
  • Complex: HER2-m66-trastuzumab
    • Protein or peptide: Trastuzumab FAB LIGHT CHAIN
    • Protein or peptide: m66 (murine-derived) HEAVY CHAIN,
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: m66 (murine-derived) HEAVY CHAIN,
    • Protein or peptide: Trastuzumab FAB HEAVY CHAIN
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
KeywordsHuman epidermal growth factor receptor 2 (HER2) / m66 (murine-derived) / r40 (rabbit-derived) / PROTEIN BINDING/IMMUNE SYSTEM / PROTEIN BINDING-IMMUNE SYSTEM complex
Function / homology
Function and homology information


ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / RNA polymerase I core binding / semaphorin receptor complex / Developmental Lineage of Mammary Stem Cells / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / regulation of microtubule-based process / PLCG1 events in ERBB2 signaling ...ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / RNA polymerase I core binding / semaphorin receptor complex / Developmental Lineage of Mammary Stem Cells / ErbB-3 class receptor binding / 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 / 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 / ERBB2-ERBB3 signaling pathway / positive regulation of MAP kinase activity / positive regulation of Rho protein signal transduction / ERBB2 Regulates Cell Motility / positive regulation of transcription by RNA polymerase I / Developmental Lineage of Mammary Gland Myoepithelial Cells / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / regulation of angiogenesis / Developmental Lineage of Mammary Gland Luminal Epithelial Cells / positive regulation of protein targeting to membrane / 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 / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / peptidyl-tyrosine phosphorylation / positive regulation of cell adhesion / GRB2 events in ERBB2 signaling / cell surface receptor protein tyrosine kinase signaling pathway / basal plasma membrane / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / Constitutive Signaling by Overexpressed ERBB2 / wound healing / Downregulation of ERBB2:ERBB3 signaling / phosphatidylinositol 3-kinase/protein kinase B signal transduction / neuromuscular junction / positive regulation of translation / Signaling by ERBB2 TMD/JMD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / positive regulation of JNK cascade / cellular response to growth factor stimulus / epidermal growth factor receptor signaling pathway / ruffle membrane / cell population proliferation / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / neuron differentiation / PIP3 activates AKT signaling / myelin sheath / positive regulation of cell growth / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / presynaptic membrane / basolateral plasma membrane / early endosome / protein phosphorylation / positive regulation of MAPK cascade / cell surface receptor signaling pathway / signaling receptor complex / postsynaptic membrane / intracellular signal transduction / apical plasma membrane / endosome membrane / 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 / 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 / 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 speciesChimeric Dengue virus vector p4(Delta30)-D2-ME / Homo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLiu C / Ren Y / Luo X / Zhou P / Du X / Wang Q / Han X / Xu Y / Wang P / Zhao D / Yang H
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: PLoS One / Year: 2026
Title: Inhibition of HER2 signaling and breast cancer cell growth with a novel antibody targeting HER2 ECD III/IV.
Authors: Chunchun Liu / Yulei Ren / Xuan Luo / Peiyun Zhou / Xiangjuan Du / Qianmin Wang / Xue Han / Yanhui Xu / Ping Wang / Dan Zhao / Huirong Yang /
Abstract: Human epidermal growth factor receptor 2 (HER2), a ligand-independent tyrosine kinase receptor belonging to the EGFR family, serves as a key oncogenic driver in breast, gastric, and several other ...Human epidermal growth factor receptor 2 (HER2), a ligand-independent tyrosine kinase receptor belonging to the EGFR family, serves as a key oncogenic driver in breast, gastric, and several other solid tumors. Although anti-HER2 therapies have substantially improved survival outcomes-particularly in breast and gastric cancers-treatment resistance and cancer recurrence remain major clinical challenges. Thus, developing novel antibodies exhibiting complementary effects to the current anti-HER2 therapies could provide additional therapeutic benefits. Here, we describe two novel HER2-targeting monoclonal antibodies, m66 (murine-derived) and r40 (rabbit-derived), which inhibit breast cancer cell proliferation in vitro. Of the two, antibody r40 exhibits stronger suppression of the PI3K/AKT and MAPK signaling pathways compared to m66. Moreover, the addition of r40 to the combination of trastuzumab and pertuzumab leads to a significantly enhanced inhibitory effect. We also determined the cryo-EM structures of the HER2-m66-trastuzumab ternary complex and the HER2-r40-trastuzumab-pertuzumab tetrameric complex, at overall resolutions of 3.2 Å and 3.1 Å, respectively. Structural analyses reveal that m66 recognizes an epitope overlapping with that of pertuzumab, whereas r40 binds within the HER2 ECD III/IV-a region distinct from the binding sites of both trastuzumab and pertuzumab. These findings identify r40 as a promising therapeutic candidate for use in combination with trastuzumab and pertuzumab in the treatment of HER2-positive breast cancer.
History
DepositionJan 9, 2026-
Header (metadata) releaseOct 28, 2026-
Map releaseOct 28, 2026-
UpdateOct 28, 2026-
Current statusOct 28, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_68255.png

Downloads & links

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Map

FileDownload / File: emd_68255.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNone
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 256 pix.
= 238.592 Å		0.93 Å/pix.
x 256 pix.
= 238.592 Å		0.93 Å/pix.
x 256 pix.
= 238.592 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.932 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00351
Minimum - Maximum-0.028868329 - 0.052180633
Average (Standard dev.)-0.000010557054 (±0.0012101236)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.592 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: None

Fileemd_68255_half_map_1.map
AnnotationNone
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: None

Fileemd_68255_half_map_2.map
AnnotationNone
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : HER2-m66-trastuzumab

EntireName: HER2-m66-trastuzumab
Components
  • Complex: HER2-m66-trastuzumab
    • Protein or peptide: Trastuzumab FAB LIGHT CHAIN
    • Protein or peptide: m66 (murine-derived) HEAVY CHAIN,
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: m66 (murine-derived) HEAVY CHAIN,
    • Protein or peptide: Trastuzumab FAB HEAVY CHAIN
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2

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Supramolecule #1: HER2-m66-trastuzumab

SupramoleculeName: HER2-m66-trastuzumab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Chimeric Dengue virus vector p4(Delta30)-D2-ME

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Macromolecule #1: Trastuzumab FAB LIGHT CHAIN

MacromoleculeName: Trastuzumab FAB LIGHT CHAIN / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.131178 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GAPDIQMTQS PASLSASVGE TVTITCRASE NIYSFLAWYQ QKQGKSPQLL VYNAKTLGEG VPSRFSGSGS GTQFSLKINS LQPEDFGIY YCQHHYGTPF TFGAGTKLEL KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE ...String:
GAPDIQMTQS PASLSASVGE TVTITCRASE NIYSFLAWYQ QKQGKSPQLL VYNAKTLGEG VPSRFSGSGS GTQFSLKINS LQPEDFGIY YCQHHYGTPF TFGAGTKLEL KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGECG GSRGVPHIVM VDAYKRYK (END)

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Macromolecule #2: m66 (murine-derived) HEAVY CHAIN,

MacromoleculeName: m66 (murine-derived) HEAVY CHAIN, / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 25.909957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GTQIQLVQSG PELKKPGETV KIACKASGYT FTTYGMSWVK QAPGKGVKWM GWINTYSGVP TYADDFKGRF AFSLETSAST AYLQINNLK KEDTATYFCA REGHYDYSYA MDYWGQGTSV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA ...String:
GTQIQLVQSG PELKKPGETV KIACKASGYT FTTYGMSWVK QAPGKGVKWM GWINTYSGVP TYADDFKGRF AFSLETSAST AYLQINNLK KEDTATYFCA REGHYDYSYA MDYWGQGTSV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEPKSCGS HHHHHHHHH (END)

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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: 39.562805 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: TACPYNYLST DVGSCTLVCP LHNQEVTAED GTQRCEKCSK PCARVCYGLG MEHLREVRAV TSANIQEFAG CKKIFGSLAF LPESFDGDP ASNTAPLQPE QLQVFETLEE ITGYLYISAW PDSLPDLSVF QNLQVIRGRI LHNGAYSLTL QGLGISWLGL R SLRELGSG ...String:
TACPYNYLST DVGSCTLVCP LHNQEVTAED GTQRCEKCSK PCARVCYGLG MEHLREVRAV TSANIQEFAG CKKIFGSLAF LPESFDGDP ASNTAPLQPE QLQVFETLEE ITGYLYISAW PDSLPDLSVF QNLQVIRGRI LHNGAYSLTL QGLGISWLGL R SLRELGSG LALIHHNTHL CFVHTVPWDQ LFRNPHQALL HTANRPEDEC VGEGLACHQL CARGHCWGPG PTQCVNCSQF LR GQECVEE CRVLQGLPRE YVNARHCLPC HPECQPQNGS VTCFGPEADQ CVACAHYKDP PFCVARCPSG VKPDLSYMPI WKF PDEEGA CQPCPINCTH SCVDLDDKGC PAEQRASPLT (END)

UniProtKB: Receptor tyrosine-protein kinase erbB-2

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Macromolecule #4: m66 (murine-derived) HEAVY CHAIN,

MacromoleculeName: m66 (murine-derived) HEAVY CHAIN, / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.134135 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GAPDIQMTQS PSSLSASVGD RVTITCRASQ DVNTAVAWYQ QKPGKAPKLL IYSASFLYSG VPSRFSGSRS GTDFTLTISS LQPEDFATY YCQQHYTTPP TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE ...String:
GAPDIQMTQS PSSLSASVGD RVTITCRASQ DVNTAVAWYQ QKPGKAPKLL IYSASFLYSG VPSRFSGSRS GTDFTLTISS LQPEDFATY YCQQHYTTPP TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGECG GSRGVPHIVM VDAYKRYK (END)

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Macromolecule #5: Trastuzumab FAB HEAVY CHAIN

MacromoleculeName: Trastuzumab FAB HEAVY CHAIN / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.612539 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GTEVQLVESG GGLVQPGGSL RLSCAASGFN IKDTYIHWVR QAPGKGLEWV ARIYPTNGYT RYADSVKGRF TISADTSKNT AYLQMNSLR AEDTAVYYCS RWGGDGFYAM DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
GTEVQLVESG GGLVQPGGSL RLSCAASGFN IKDTYIHWVR QAPGKGLEWV ARIYPTNGYT RYADSVKGRF TISADTSKNT AYLQMNSLR AEDTAVYYCS RWGGDGFYAM DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCGSH HHHHHHHH (END)

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Macromolecule #6: Receptor tyrosine-protein kinase erbB-2

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.829355 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPGGSRGVPH IVMVDAYKRY KGGSDYKDDD DKGTTQVCTG TDMKLRLPAS PETHLDMLRH LYQGCQVVQG NLELTYLPTN ASLSFLQDI QEVQGYVLIA HNQVRQVPLQ RLRIVRGTQL FEDNYALAVL DNGDPLNNTT PVTGASPGGL RELQLRSLTE I LKGGVLIQ ...String:
GPGGSRGVPH IVMVDAYKRY KGGSDYKDDD DKGTTQVCTG TDMKLRLPAS PETHLDMLRH LYQGCQVVQG NLELTYLPTN ASLSFLQDI QEVQGYVLIA HNQVRQVPLQ RLRIVRGTQL FEDNYALAVL DNGDPLNNTT PVTGASPGGL RELQLRSLTE I LKGGVLIQ RNPQLCYQDT ILWKDIFHKN NQLALTLIDT NRSRACHPCS PMCKGSRCWG ESSEDCQSLT RTVCAGGCAR CK GPLPTDC CHEQCAAGCT GPKHSDCLAC LHFNHSGICE LHCPALVTYN TDTFESMPNP EGRYTFGASC V

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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6oge

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 282644
Initial angle assignmentType: OTHER
Final angle assignmentType: ANGULAR RECONSTITUTION

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