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- EMDB-29044: Structure of Zanidatamab bound to HER2 -

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Basic information

Entry
Database: EMDB / ID: EMD-29044
TitleStructure of Zanidatamab bound to HER2
Map datacryosparc refined map
Sample
  • Complex: Complex of Zanidatamab and HER2
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Zanidatamab Heavy Chain A
    • Protein or peptide: Zanidatamab Light Chain A
    • Protein or peptide: Zanidatamab Heavy Chain B
KeywordsAntibody / biparatopic / 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 / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / ErbB-3 class receptor binding / regulation of microtubule-based process / 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 / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / ErbB-3 class receptor binding / regulation of microtubule-based process / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / PLCG1 events in ERBB2 signaling / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2-EGFR signaling pathway / positive regulation of Rho protein signal transduction / ERBB2 Activates PTK6 Signaling / neuromuscular junction development / positive regulation of transcription by RNA polymerase I / 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 / enzyme-linked receptor protein signaling pathway / ERBB2-ERBB3 signaling pathway / 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 / coreceptor activity / Schwann cell development / cell surface receptor protein tyrosine kinase signaling pathway / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / positive regulation of cell adhesion / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / neurogenesis / positive regulation of epithelial cell proliferation / basal plasma membrane / positive regulation of translation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / neuromuscular junction / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / neuron differentiation / cellular response to growth factor stimulus / receptor tyrosine kinase binding / Downregulation of ERBB2 signaling / peptidyl-tyrosine phosphorylation / ruffle membrane / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / heart development / presynaptic membrane / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / positive regulation of MAPK cascade / early endosome / receptor complex / cell surface receptor signaling pathway / endosome membrane / intracellular signal transduction / protein heterodimerization activity / positive regulation of protein phosphorylation / protein phosphorylation / apical plasma membrane / signaling receptor binding / positive regulation of cell population proliferation / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / identical protein binding / membrane / nucleus / plasma membrane
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: 7.5 Å
AuthorsWorrall LJ / Atkinson CE / Sanches M / Dixit S / Strynadka NCJ
Funding support Canada, 1 items
OrganizationGrant numberCountry
Not funded Canada
CitationJournal: Nat Commun / Year: 2023
Title: An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.
Authors: Nina E Weisser / Mario Sanches / Eric Escobar-Cabrera / Jason O'Toole / Elizabeth Whalen / Peter W Y Chan / Grant Wickman / Libin Abraham / Kate Choi / Bryant Harbourne / Antonios Samiotakis ...Authors: Nina E Weisser / Mario Sanches / Eric Escobar-Cabrera / Jason O'Toole / Elizabeth Whalen / Peter W Y Chan / Grant Wickman / Libin Abraham / Kate Choi / Bryant Harbourne / Antonios Samiotakis / Andrea Hernández Rojas / Gesa Volkers / Jodi Wong / Claire E Atkinson / Jason Baardsnes / Liam J Worrall / Duncan Browman / Emma E Smith / Priya Baichoo / Chi Wing Cheng / Joy Guedia / Sohyeong Kang / Abhishek Mukhopadhyay / Lisa Newhook / Anders Ohrn / Prajwal Raghunatha / Matteo Zago-Schmitt / Joseph D Schrag / Joel Smith / Patricia Zwierzchowski / Joshua M Scurll / Vincent Fung / Sonia Black / Natalie C J Strynadka / Michael R Gold / Leonard G Presta / Gordon Ng / Surjit Dixit /
Abstract: Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently ...Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.
History
DepositionDec 8, 2022-
Header (metadata) releaseFeb 22, 2023-
Map releaseFeb 22, 2023-
UpdateSep 4, 2024-
Current statusSep 4, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29044.png

Downloads & links

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Map

FileDownload / File: emd_29044.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryosparc refined map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.4 Å/pix.
x 256 pix.
= 358.4 Å		1.4 Å/pix.
x 256 pix.
= 358.4 Å		1.4 Å/pix.
x 256 pix.
= 358.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.4 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.081728 - 2.9249535
Average (Standard dev.)0.0025737681 (±0.08785227)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 358.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: cryosparc refined half map

Fileemd_29044_half_map_1.map
Annotationcryosparc refined half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryosparc refined half map

Fileemd_29044_half_map_2.map
Annotationcryosparc refined half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of Zanidatamab and HER2

EntireName: Complex of Zanidatamab and HER2
Components
  • Complex: Complex of Zanidatamab and HER2
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Zanidatamab Heavy Chain A
    • Protein or peptide: Zanidatamab Light Chain A
    • Protein or peptide: Zanidatamab Heavy Chain B

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Supramolecule #1: Complex of Zanidatamab and HER2

SupramoleculeName: Complex of Zanidatamab and HER2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Receptor tyrosine-protein kinase erbB-2

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2 / 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: 68.536844 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
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 DLDDKGCPA

UniProtKB: Receptor tyrosine-protein kinase erbB-2

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Macromolecule #2: Zanidatamab Heavy Chain A

MacromoleculeName: Zanidatamab Heavy Chain A / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.217211 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: GEVQLVESGG GLVQPGGSLR LSCAASGFTF TDYTMDWVRQ APGKGLEWVA DVNPNSGGSI YNQRFKGRFT LSVDRSKNTL YLQMNSLRA EDTAVYYCAR NLGPSFYFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
GEVQLVESGG GLVQPGGSLR LSCAASGFTF TDYTMDWVRQ APGKGLEWVA DVNPNSGGSI YNQRFKGRFT LSVDRSKNTL YLQMNSLRA EDTAVYYCAR NLGPSFYFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKTHT CPPCPAPELL GG PSVFLFP PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS VLTVLHQDWL NGK EYKCKV SNKALPAPIE KTISKAKGQP REPQVYVYPP SRDELTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPV LDSDG SFALVSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGGS

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Macromolecule #3: Zanidatamab Light Chain A

MacromoleculeName: Zanidatamab Light Chain A / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.749334 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: GDIQMTQSPS SLSASVGDRV TITCKASQDV SIGVAWYQQK PGKAPKLLIY SASYRYTGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYC QQYYIYPYTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
GDIQMTQSPS SLSASVGDRV TITCKASQDV SIGVAWYQQK PGKAPKLLIY SASYRYTGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYC QQYYIYPYTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGECGS

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Macromolecule #4: Zanidatamab Heavy Chain B

MacromoleculeName: Zanidatamab Heavy Chain B / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.5415 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: GDIQMTQSPS SLSASVGDRV TITCRASQDV NTAVAWYQQK PGKAPKLLIY SASFLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQHYTTPPTF GQGTKVEIKG GSGGGSGGGS GGGSGGGSGE VQLVESGGGL VQPGGSLRLS CAASGFNIKD T YIHWVRQA ...String:
GDIQMTQSPS SLSASVGDRV TITCRASQDV NTAVAWYQQK PGKAPKLLIY SASFLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQHYTTPPTF GQGTKVEIKG GSGGGSGGGS GGGSGGGSGE VQLVESGGGL VQPGGSLRLS CAASGFNIKD T YIHWVRQA PGKGLEWVAR IYPTNGYTRY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCSRWG GDGFYAMDYW GQ GTLVTVS SAAEPKSSDK THTCPPCPAP ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVH NAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYVL PPSRDELTKN QVSL LCLVK GFYPSDIAVE WESNGQPENN YLTWPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSP GGS

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: INTEGRATING / Average electron dose: 110.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionNumber classes used: 1 / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 7.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 27589
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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