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- EMDB-34744: The EGF-bound EGFR/HER2 ectodomain complex -

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Basic information

Entry
Database: EMDB / ID: EMD-34744
TitleThe EGF-bound EGFR/HER2 ectodomain complex
Map data
Sample
  • Complex: EGF-bound EGFR/HER2 ectodomain complex
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Epidermal growth factor receptor
    • Protein or peptide: Epidermal growth factor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of hyaluronan biosynthetic process / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / PLCG1 events in ERBB2 signaling / positive regulation of cerebellar granule cell precursor proliferation / ERBB2-ERBB4 signaling pathway ...Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of hyaluronan biosynthetic process / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / PLCG1 events in ERBB2 signaling / positive regulation of cerebellar granule cell precursor proliferation / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / cerebellar granule cell precursor proliferation / immature T cell proliferation in thymus / RNA polymerase I core binding / ERBB2-EGFR signaling pathway / positive regulation of epithelial tube formation / ERBB2 Activates PTK6 Signaling / regulation of calcium ion import / positive regulation of protein localization to early endosome / regulation of protein localization to cell surface / semaphorin receptor complex / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / Signaling by ERBB4 / positive regulation of ubiquitin-dependent protein catabolic process / regulation of microtubule-based process / ErbB-3 class receptor binding / ERBB2 Regulates Cell Motility / Sema4D induced cell migration and growth-cone collapse / Differentiation of keratinocytes in interfollicular epidermis in mammalian skin / motor neuron axon guidance / PI3K events in ERBB2 signaling / regulation of receptor signaling pathway via JAK-STAT / neurotransmitter receptor localization to postsynaptic specialization membrane / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / NFE2L2 regulating tumorigenic genes / positive regulation of Rho protein signal transduction / epidermal growth factor receptor binding / neuromuscular junction development / branching morphogenesis of an epithelial tube / positive regulation of DNA binding / 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 / GAB1 signalosome / enzyme-linked receptor protein signaling pathway / ERBB2-ERBB3 signaling pathway / positive regulation of transcription by RNA polymerase I / oligodendrocyte differentiation / positive regulation of phosphorylation / positive regulation of receptor internalization / semaphorin-plexin signaling pathway / cellular response to epidermal growth factor stimulus / Signaling by ERBB2 / positive regulation of cell adhesion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of protein targeting to membrane / Complex I biogenesis / mammary gland alveolus development / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / regulation of angiogenesis / neurogenesis / Respiratory electron transport / SHC1 events in ERBB2 signaling / coreceptor activity / regulation of ERK1 and ERK2 cascade / Schwann cell development / basal plasma membrane / positive regulation of epithelial cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / epithelial cell proliferation / positive regulation of endothelial cell proliferation / ERK1 and ERK2 cascade / myelination / NOTCH3 Activation and Transmission of Signal to the Nucleus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Downregulation of ERBB2:ERBB3 signaling / positive regulation of endothelial cell migration / Constitutive Signaling by Overexpressed ERBB2 / positive regulation of mitotic nuclear division / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / platelet alpha granule lumen / guanyl-nucleotide exchange factor activity / : / positive regulation of peptidyl-threonine phosphorylation / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / mitochondrial electron transport, NADH to ubiquinone
Similarity search - Function
Pro-epidermal growth factor / : / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat ...Pro-epidermal growth factor / : / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / : / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Calcium-binding EGF domain / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Six-bladed beta-propeller, TolB-like / Coagulation Factor Xa inhibitory site / EGF-like domain / NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Zinc finger, CHCC-type / Zinc-finger domain / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Growth factor receptor cysteine-rich domain superfamily / : / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / 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
NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial / Pro-epidermal growth factor / Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsZhang Z / Bai X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171201 China
CitationJournal: Cell Discov / Year: 2023
Title: Structure and dynamics of the EGFR/HER2 heterodimer.
Authors: Xue Bai / Pengyu Sun / Xinghao Wang / Changkun Long / Shuyun Liao / Song Dang / Shangshang Zhuang / Yongtao Du / Xinyi Zhang / Nan Li / Kangmin He / Zhe Zhang /
Abstract: HER2 belongs to the human epidermal growth factor receptor tyrosine kinase family. Its overexpression or hyperactivation is a leading cause for multiple types of cancers. HER2 functions mainly ...HER2 belongs to the human epidermal growth factor receptor tyrosine kinase family. Its overexpression or hyperactivation is a leading cause for multiple types of cancers. HER2 functions mainly through dimerization with other family members, such as EGFR. However, the molecular details for heterodimer assembly have not been completely understood. Here, we report cryo-EM structures of the EGF- and epiregulin-bound EGFR/HER2 ectodomain complexes at resolutions of 3.3 Å and 4.5 Å, respectively. Together with the functional analyses, we demonstrate that only the dimerization arm of HER2, but not that of EGFR, is essential for their heterodimer formation and signal transduction. Moreover, we analyze the differential membrane dynamics and transient interactions of endogenous EGFR and HER2 molecules in genome-edited cells using single-molecule live-cell imaging. Furthermore, we show that the interaction with HER2 could allow EGFR to resist endocytosis. Together, this work deepens our understanding of the unique structural properties and dynamics of the EGFR/HER2 complex.
History
DepositionNov 15, 2022-
Header (metadata) releaseFeb 8, 2023-
Map releaseFeb 8, 2023-
UpdateMar 1, 2023-
Current statusMar 1, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34744.png

Downloads & links

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Map

FileDownload / File: emd_34744.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0017529412 - 1.961597
Average (Standard dev.)0.00030572535 (±0.012938216)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 410.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_34744_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_34744_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : EGF-bound EGFR/HER2 ectodomain complex

EntireName: EGF-bound EGFR/HER2 ectodomain complex
Components
  • Complex: EGF-bound EGFR/HER2 ectodomain complex
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Epidermal growth factor receptor
    • Protein or peptide: Epidermal growth factor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: EGF-bound EGFR/HER2 ectodomain complex

SupramoleculeName: EGF-bound EGFR/HER2 ectodomain complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 200 KDa

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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: 82.149758 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MELAALCRWG LLLALLPPGA ASTQVCTGTD MKLRLPASPE THLDMLRHLY QGCQVVQGNL ELTYLPTNAS LSFLQDIQEV QGYVLIAHN QVRQVPLQRL RIVRGTQLFE DNYALAVLDN GDPLNNTTPV TGASPGGLRE LQLRSLTEIL KGGVLIQRNP Q LCYQDTIL ...String:
MELAALCRWG LLLALLPPGA ASTQVCTGTD MKLRLPASPE THLDMLRHLY QGCQVVQGNL ELTYLPTNAS LSFLQDIQEV QGYVLIAHN QVRQVPLQRL RIVRGTQLFE DNYALAVLDN GDPLNNTTPV TGASPGGLRE LQLRSLTEIL KGGVLIQRNP Q LCYQDTIL WKDIFHKNNQ LALTLIDTNR SRACHPCSPM CKGSRCWGES SEDCQSLTRT VCAGGCARCK GPLPTDCCHE QC AAGCTGP KHSDCLACLH FNHSGICELH CPALVTYNTD TFESMPNPEG RYTFGASCVT ACPYNYLSTD VGSCTLVCPL HNQ EVTAED GTQRCEKCSK PCARVCYGLG MEHLREVRAV TSANIQEFAG CKKIFGSLAF LPESFDGDPA SNTAPLQPEQ LQVF ETLEE ITGYLYISAW PDSLPDLSVF QNLQVIRGRI LHNGAYSLTL QGLGISWLGL RSLRELGSGL ALIHHNTHLC FVHTV PWDQ LFRNPHQALL HTANRPEDEC VGEGLACHQL CARGHCWGPG PTQCVNCSQF LRGQECVEEC RVLQGLPREY VNARHC LPC HPECQPQNGS VTCFGPEADQ CVACAHYKDP PFCVARCPSG VKPDLSYMPI WKFPDEEGAC QPCPINCTHS CVDLDDK GC PAEQRASPLT SIISAVVGIL LVVVLGVVFG ILIKRRQQKI RKYTMRRLLQ EGGSENLYFQ GGGSAQLEKE LQALEKEN A QLEWELQALE KELAQSNSLE VLFQ

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Macromolecule #2: Epidermal growth factor receptor

MacromoleculeName: Epidermal growth factor receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 81.075297 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYV LIALNTVERI PLENLQIIRG NMYYENSYAL AVLSNYDANK TGLKELPMRN LQEILHGAVR FSNNPALCNV E SIQWRDIV ...String:
MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYV LIALNTVERI PLENLQIIRG NMYYENSYAL AVLSNYDANK TGLKELPMRN LQEILHGAVR FSNNPALCNV E SIQWRDIV SSDFLSNMSM DFQNHLGSCQ KCDPSCPNGS CWGAGEENCQ KLTKIICAQQ CSGRCRGKSP SDCCHNQCAA GC TGPRESD CLVCRKFRDE ATCKDTCPPL MLYNPTTYQM DVNPEGKYSF GATCVKKCPR NYVVTDHGSC VRACGADSYE MEE DGVRKC KKCEGPCRKV CNGIGIGEFK DSLSINATNI KHFKNCTSIS GDLHILPVAF RGDSFTHTPP LDPQELDILK TVKE ITGFL LIQAWPENRT DLHAFENLEI IRGRTKQHGQ FSLAVVSLNI TSLGLRSLKE ISDGDVIISG NKNLCYANTI NWKKL FGTS GQKTKIISNR GENSCKATGQ VCHALCSPEG CWGPEPRDCV SCRNVSRGRE CVDKCNLLEG EPREFVENSE CIQCHP ECL PQAMNITCTG RGPDNCIQCA HYIDGPHCVK TCPAGVMGEN NTLVWKYADA GHVCHLCHPN CTYGCTGPGL EGCPTNG PK IPSIATGMVG ALLLLLVVAL GIGLFMRRRH IVRKRTLRRL LGGSENLYFQ GGGSAAQLKK KLQALKKKNA QLKWKLQA L KKKLAQSNSL EVLFQ

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Macromolecule #3: Epidermal growth factor

MacromoleculeName: Epidermal growth factor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.555376 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GPTANSDSEC PLSHDGYCLH DGVCMYIEAL DKYACNCVVG YIGERCQYRD LKWWELR

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration4.2 mg/mL
BufferpH: 7.5 / Details: 25mM Hepes, 150mM NaCl, 0.02%DDM-0.002%CHS
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 207092
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8hgo:
The EGF-bound EGFR/HER2 ectodomain complex

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