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

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Basic information

Entry
Database: PDB / ID: 8hgo
TitleThe EGF-bound EGFR/HER2 ectodomain complex
Components
  • (Epidermal growth ...) x 2
  • Receptor tyrosine-protein kinase erbB-2
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / positive regulation of cerebellar granule cell precursor proliferation / negative regulation of cholesterol efflux / cerebellar granule cell precursor proliferation / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / regulation of protein localization to cell surface ...positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / positive regulation of cerebellar granule cell precursor proliferation / negative regulation of cholesterol efflux / cerebellar granule cell precursor proliferation / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / regulation of protein localization to cell surface / positive regulation of protein localization to early endosome / regulation of calcium ion import / RNA polymerase I core binding / positive regulation of epithelial tube formation / semaphorin receptor complex / transmembrane receptor protein tyrosine kinase activator activity / Developmental Lineage of Mammary Stem Cells / Developmental Lineage of Mammary Gland Luminal Epithelial Cells / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / regulation of microtubule-based process / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / morphogenesis of an epithelial fold / positive regulation of peptidyl-threonine phosphorylation / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / positive regulation of DNA binding / EGFR interacts with phospholipase C-gamma / NFE2L2 regulating tumorigenic genes / digestive tract morphogenesis / positive regulation of ubiquitin-dependent protein catabolic process / branching morphogenesis of an epithelial tube / epidermal growth factor receptor binding / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation / ubiquitin-dependent endocytosis / regulation of receptor signaling pathway via JAK-STAT / PLCG1 events in ERBB2 signaling / cerebral cortex cell migration / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / enzyme-linked receptor protein signaling pathway / eyelid development in camera-type eye / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / mammary gland alveolus development / hair follicle development / 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 / neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of MAP kinase activity / positive regulation of Rho protein signal transduction / intracellular vesicle / positive regulation of transcription by RNA polymerase I / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / embryonic placenta development / negative regulation of epidermal growth factor receptor signaling pathway / protein insertion into membrane / semaphorin-plexin signaling pathway / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of receptor internalization / regulation of angiogenesis / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / epithelial cell proliferation / positive regulation of protein targeting to membrane / GAB1 signalosome / regulation of ERK1 and ERK2 cascade / ERK1 and ERK2 cascade / xenobiotic transport / salivary gland morphogenesis / positive regulation of G1/S transition of mitotic cell cycle / Schwann cell development / positive regulation of epidermal growth factor receptor signaling pathway / coreceptor activity / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of mitotic nuclear division
Similarity search - Function
Pro-epidermal growth factor / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / : / Calcium-binding EGF domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment ...Pro-epidermal growth factor / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / : / Calcium-binding EGF 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 / Six-bladed beta-propeller, TolB-like / Coagulation Factor Xa inhibitory site / EGF-like domain / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / EGF-type aspartate/asparagine hydroxylation site / Furin-like repeat / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Furin-like repeats / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / : / EGF-like domain / 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
Epidermal growth factor receptor / Pro-epidermal growth factor / Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsZhang, Z. / Bai, X.
Funding support China, 1items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Receptor tyrosine-protein kinase erbB-2
A: Epidermal growth factor receptor
C: Epidermal growth factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,3967
Polymers169,7803
Non-polymers1,6154
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 1 molecules B

#1: 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: 82149.758 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 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human)
References: UniProt: P04626, receptor protein-tyrosine kinase

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Epidermal growth ... , 2 types, 2 molecules AC

#2: Protein Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 81075.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human)
References: UniProt: P00533, receptor protein-tyrosine kinase
#3: Protein Epidermal growth factor / Urogastrone


Mass: 6555.376 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGF / Production host: Escherichia coli (E. coli) / References: UniProt: P01133

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Sugars , 3 types, 4 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-3DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b3-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(3+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestY
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: EGF-bound EGFR/HER2 ectodomain complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.2 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S GnTI-
Buffer solutionpH: 7.5 / Details: 25mM Hepes, 150mM NaCl, 0.02%DDM-0.002%CHS
SpecimenConc.: 4.2 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: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
7UCSF ChimeraXmodel fitting
10cryoSPARCfinal Euler assignment
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 207092 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039475
ELECTRON MICROSCOPYf_angle_d0.70212887
ELECTRON MICROSCOPYf_dihedral_angle_d11.7695828
ELECTRON MICROSCOPYf_chiral_restr0.0531425
ELECTRON MICROSCOPYf_plane_restr0.0071683

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