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- EMDB-43439: HER2 S310F in complex with TL1 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-43439
TitleHER2 S310F in complex with TL1 Fab
Map dataMap generated after local refinement
Sample
  • Complex: HER2 S310F in complex with TL1 Fab
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion
    • Protein or peptide: Variable Heavy chain of TL1 Fab
    • Protein or peptide: Variable Light chain of TL1 Fab
KeywordsHER2 / Fab / Tyrosine kinase receptor / 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 / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / 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 / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / neuromuscular junction development / ERBB2 Activates PTK6 Signaling / enzyme-linked receptor protein signaling pathway / 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 transcription by RNA polymerase I / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / Schwann cell development / regulation of ERK1 and ERK2 cascade / coreceptor activity / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / positive regulation of MAP kinase activity / GRB2 events in ERBB2 signaling / positive regulation of cell adhesion / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of epithelial cell proliferation / basal plasma membrane / positive regulation of translation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / Signaling by ERBB2 TMD/JMD mutants / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / neuromuscular junction / cellular response to growth factor stimulus / peptidyl-tyrosine phosphorylation / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / epidermal growth factor receptor signaling pathway / ruffle membrane / Downregulation of ERBB2 signaling / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / presynaptic membrane / heart development / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / early endosome / cell population proliferation / receptor complex / cell surface receptor signaling pathway / positive regulation of MAPK cascade
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 speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsBang I / Koide S
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Chem Biol / Year: 2025
Title: Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain.
Authors: Injin Bang / Takamitsu Hattori / Nadia Leloup / Alexis Corrado / Atekana Nyamaa / Akiko Koide / Ken Geles / Elizabeth Buck / Shohei Koide /
Abstract: Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been ...Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.
History
DepositionJan 18, 2024-
Header (metadata) releaseOct 9, 2024-
Map releaseOct 9, 2024-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43439.png

Downloads & links

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Map

FileDownload / File: emd_43439.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap generated after local refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 316.8 Å		0.83 Å/pix.
x 384 pix.
= 316.8 Å		0.83 Å/pix.
x 384 pix.
= 316.8 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.18
Minimum - Maximum-0.48761857 - 0.9681529
Average (Standard dev.)0.00039583707 (±0.016271558)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 316.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_43439_msk_1.map
Projections & Slices
AxesZYX

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Half map: Half map A

Fileemd_43439_half_map_1.map
AnnotationHalf map A
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_43439_half_map_2.map
AnnotationHalf map B
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Sample components

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Entire : HER2 S310F in complex with TL1 Fab

EntireName: HER2 S310F in complex with TL1 Fab
Components
  • Complex: HER2 S310F in complex with TL1 Fab
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion
    • Protein or peptide: Variable Heavy chain of TL1 Fab
    • Protein or peptide: Variable Light chain of TL1 Fab

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Supramolecule #1: HER2 S310F in complex with TL1 Fab

SupramoleculeName: HER2 S310F in complex with TL1 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Fab that only binds to HER2 S310F/Y but not to WT is in complex with HER2 S310F
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 150 kDa/nm

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Macromolecule #1: Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 99.261641 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 ALVTFNTDTF ESMPNPEGRY TFGASCVTAC PYNYLSTDVG FCTLVCPLHN 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 QRASPLTPGS RSPKSCD KT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYR V VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP PSREEMTKNQ VSLTCLVKGF YPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGKLEGG GGLNDIFEAQ KIEWHESRH HHHHH

UniProtKB: Receptor tyrosine-protein kinase erbB-2

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Macromolecule #2: Variable Heavy chain of TL1 Fab

MacromoleculeName: Variable Heavy chain of TL1 Fab / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.512574 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF TWSGAYIHWV RQAPGKGLEW VASIYSAGGY TDYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYGTYELKS YGSWESLPAF DYWGQGTLVT VFNQIKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF TWSGAYIHWV RQAPGKGLEW VASIYSAGGY TDYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYGTYELKS YGSWESLPAF DYWGQGTLVT VFNQIKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TG GGGLNDI FEAQKIEWHE

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Macromolecule #3: Variable Light chain of TL1 Fab

MacromoleculeName: Variable Light chain of TL1 Fab / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.3399 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QSEWGGLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QSEWGGLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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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

Concentration1.4 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMC4H11NO3Tris
0.7 mMC20H25F13O11Fluorinated Octyl Maloside

Details: 20mM Tris, 150mM NaCl, 0.7mM fluorinated octyl maltoside
GridModel: Quantifoil R0.6/1 / Material: COPPER / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 35 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.027 kPa
Details: The grid was coated with goldfoil prior and discharged with current at 15mA for 25s, held for 10s.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Details: Vitrification carried out with blot force 5, blot time 4 s.
DetailsThis sample was was eluted as a monodisperse peak with gel filtration

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 8985 / Average exposure time: 2.0 sec. / Average electron dose: 57.43 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: 2.4 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.2.1) / Software - details: PatchCTF / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Details: Combination of PDB entry (7MN6) and in silico model generated using SWISS-MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2.1) / Software - details: Local refinment / Number images used: 161060
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Details: CryoSPARC ab-initio
Final angle assignmentType: MAXIMUM LIKELIHOOD / Details: CryoSPARC local refinement

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Atomic model buiding 1

Initial model
PDB IDChain

7mn6

chain_id: B, residue_range: 23-542, source_name: PDB, initial_model_type: experimental model
source_name: SwissModel, initial_model_type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8vqd:
HER2 S310F in complex with TL1 Fab

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