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Yorodumi- PDB-7sz5: Cryo-EM structure of the extracellular module of the full-length ... -
+Open data
-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 | |||||||||
Components |
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Keywords | SIGNALING PROTEIN / receptor tyrosine kinases / epidermal growth factor receptor | |||||||||
Function / homology | Function and homology information 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 / ovulation cycle ...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 / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / COPII-mediated vesicle transport / 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 / regulation of nitric-oxide synthase activity / epidermal growth factor receptor binding / ERBB2 Activates PTK6 Signaling / morphogenesis of an epithelial fold / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / positive regulation of cell division / positive regulation of cyclin-dependent protein serine/threonine kinase activity / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of bone resorption / mammary gland alveolus development / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of glial cell proliferation / positive regulation of phosphorylation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of DNA repair / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / endoplasmic reticulum-Golgi intermediate compartment membrane / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / positive regulation of mitotic nuclear division / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / liver regeneration / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / lung development / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / growth factor activity / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
Authors | Huang, Y. / Ognjenovic, J. / Karandur, D. / Miller, K. / Merk, A. / Subramaniam, S. / Kuriyan, J. | |||||||||
Funding support | United States, 2items
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Citation | Journal: Elife / Year: 2021 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 |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7sz5.cif.gz | 245.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7sz5.ent.gz | 189.3 KB | Display | PDB format |
PDBx/mmJSON format | 7sz5.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/sz/7sz5 ftp://data.pdbj.org/pub/pdb/validation_reports/sz/7sz5 | 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 (ref.) |
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Similar structure data |
-Links
-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.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Homo sapiens (human) 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.) Homo sapiens (human) / Gene: TGFA / Production host: Escherichia coli (E. coli) / References: UniProt: P01135 |
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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 |
-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: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
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 |
-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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-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 |