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- PDB-7sz5: 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: 7sz5 | |||||||||
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Title | Cryo-EM structure of the extracellular module of the full-length EGFR bound to TGF-alpha "tips-separated" conformation | |||||||||
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![]() | SIGNALING PROTEIN / receptor tyrosine kinases / epidermal growth factor receptor | |||||||||
Function / homology | ![]() hepatocyte proliferation / Cargo concentration in the ER / response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / COPII-mediated vesicle transport ...hepatocyte proliferation / Cargo concentration in the ER / response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / COPII-mediated vesicle transport / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / epidermal growth factor receptor binding / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / regulation of JNK cascade / positive regulation of cell division / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / mammary gland alveolus development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to cadmium ion / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / positive regulation of DNA repair / transmembrane receptor protein tyrosine kinase activity / endoplasmic reticulum-Golgi intermediate compartment membrane / SHC1 events in ERBB2 signaling / neurogenesis / positive regulation of mitotic nuclear division / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / basal plasma membrane / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / positive regulation of smooth muscle cell proliferation / cellular response to amino acid stimulus / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / lung development / growth factor activity / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 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
Movie |
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 245.6 KB | Display | ![]() |
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PDB format | ![]() | 189.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 25561MC ![]() 7sydC ![]() 7syeC ![]() 7sz0C ![]() 7sz1C ![]() 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/peptide | Mass: 5560.246 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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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:TGF-alpha complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
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 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 |
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: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 102206 / Symmetry type: POINT |