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- PDB-7syd: Cryo-EM structure of the extracellular module of the full-length ... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7syd | |||||||||
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Title | Cryo-EM structure of the extracellular module of the full-length EGFR bound to EGF "tips-juxtaposed" conformation | |||||||||
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![]() | SIGNALING PROTEIN / receptor tyrosine kinases / epidermal growth factor receptor | |||||||||
Function / homology | ![]() positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of epithelial tube formation / positive regulation of cerebellar granule cell precursor proliferation / positive regulation of protein localization to early endosome / regulation of protein localization to cell surface / cerebellar granule cell precursor proliferation / regulation of calcium ion import / transmembrane receptor protein tyrosine kinase activator activity ...positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of epithelial tube formation / positive regulation of cerebellar granule cell precursor proliferation / positive regulation of protein localization to early endosome / regulation of protein localization to cell surface / cerebellar granule cell precursor proliferation / regulation of calcium ion import / transmembrane receptor protein tyrosine kinase activator activity / Developmental Lineage of Pancreatic Acinar Cells / positive regulation of ubiquitin-dependent protein catabolic process / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / epidermal growth factor receptor binding / positive regulation of protein kinase C signaling / positive regulation of peptidyl-threonine phosphorylation / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of receptor signaling pathway via JAK-STAT / regulation of peptidyl-tyrosine phosphorylation / positive regulation of DNA binding / epidermal growth factor binding / NFE2L2 regulating tumorigenic genes / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / branching morphogenesis of an epithelial tube / Signaling by EGFR / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of receptor internalization / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / mammary gland alveolus development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / ERK1 and ERK2 cascade / positive regulation of endothelial cell proliferation / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / positive regulation of endothelial cell migration / GRB2 events in ERBB2 signaling / positive regulation of mitotic nuclear division / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / guanyl-nucleotide exchange factor activity / platelet alpha granule lumen / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / growth factor activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||
![]() | Huang, Y. / Ognjenovic, J. / Karandur, D. / Miller, K. / Merk, A. / Subramaniam, S. / Kuriyan, J. | |||||||||
Funding support | ![]()
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![]() | ![]() Title: A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor. Authors: Yongjian Huang / Jana Ognjenovic / Deepti Karandur / Kate Miller / Alan Merk / Sriram Subramaniam / John Kuriyan / ![]() ![]() Abstract: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation ...The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family. | |||||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 361.2 KB | Display | ![]() |
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PDB format | ![]() | 263.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 816.7 KB | Display | ![]() |
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Full document | ![]() | 830.9 KB | Display | |
Data in XML | ![]() | 38.7 KB | Display | |
Data in CIF | ![]() | 60.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 25522MC ![]() 7syeC ![]() 7sz0C ![]() 7sz1C ![]() 7sz5C ![]() 7sz7C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 134433.328 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P00533, receptor protein-tyrosine kinase #2: Protein | Mass: 6229.027 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() Has protein modification | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: full-length human EGFR:EGF complex / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES | ||||||||||||
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Molecular weight | Experimental value: NO | ||||||||||||
Source (natural) | Organism: ![]() | ||||||||||||
Source (recombinant) |
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Buffer solution | pH: 8 | ||||||||||||
Specimen | Conc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3 | ||||||||||||
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 7500 nm / Nominal defocus min: 1500 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105728 / Symmetry type: POINT |