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- PDB-8hgs: The EGF-bound EGFR ectodomain homodimer -

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Basic information

Entry
Database: PDB / ID: 8hgs
TitleThe EGF-bound EGFR ectodomain homodimer
Components
  • Epidermal growth factor receptor
  • Pro-epidermal growth factor
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of cerebellar granule cell precursor proliferation / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / regulation of protein localization to cell surface / positive regulation of protein localization to early endosome / cerebellar granule cell precursor proliferation / regulation of calcium ion import / positive regulation of epithelial tube formation ...positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of cerebellar granule cell precursor proliferation / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / regulation of protein localization to cell surface / positive regulation of protein localization to early endosome / cerebellar granule cell precursor proliferation / regulation of calcium ion import / positive regulation of epithelial tube formation / transmembrane receptor protein tyrosine kinase activator activity / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / positive regulation of peptidyl-threonine phosphorylation / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / regulation of receptor signaling pathway via JAK-STAT / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of DNA binding / NFE2L2 regulating tumorigenic genes / positive regulation of ubiquitin-dependent protein catabolic process / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor receptor binding / response to UV-A / ubiquitin-dependent endocytosis / PLCG1 events in ERBB2 signaling / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / branching morphogenesis of an epithelial tube / digestive tract morphogenesis / ERBB2-EGFR signaling pathway / Signaling by EGFR / eyelid development in camera-type eye / intracellular vesicle / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / protein insertion into membrane / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / mammary gland alveolus development / negative regulation of epidermal growth factor receptor signaling pathway / positive regulation of receptor internalization / PI3K events in ERBB2 signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of phosphorylation / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / GAB1 signalosome / salivary gland morphogenesis / xenobiotic transport / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of epidermal growth factor receptor signaling pathway / ERK1 and ERK2 cascade / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / positive regulation of endothelial cell migration / GRB2 events in ERBB2 signaling / epithelial cell proliferation / guanyl-nucleotide exchange factor activity / platelet alpha granule lumen / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / positive regulation of epithelial cell proliferation / positive regulation of DNA repair / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / growth factor activity / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / sperm end piece / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / receptor protein-tyrosine kinase / Constitutive Signaling by EGFRvIII / cell-cell adhesion / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of protein phosphorylation
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 / Furin-like repeats / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.81 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 15, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 23, 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
A: Epidermal growth factor receptor
C: Pro-epidermal growth factor
D: Pro-epidermal growth factor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)177,64410
Polymers175,2614
Non-polymers2,3826
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13390 Å2
ΔGint-6 kcal/mol
Surface area62860 Å2

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Components

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


Mass: 81075.297 Da / Num. of mol.: 2
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
#2: Protein Pro-epidermal growth factor


Mass: 6555.376 Da / Num. of mol.: 2
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
#3: 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.: 2
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
#4: 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.: 4 / 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
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 ectodomain homodimer / Type: COMPLEX / Entity ID: #1-#2 / 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
SpecimenConc.: 4.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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
9PHENIXmodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 196557 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310340
ELECTRON MICROSCOPYf_angle_d0.73214036
ELECTRON MICROSCOPYf_dihedral_angle_d9.1066224
ELECTRON MICROSCOPYf_chiral_restr0.0551550
ELECTRON MICROSCOPYf_plane_restr0.0061820

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