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Yorodumi- PDB-7syd: Cryo-EM structure of the extracellular module of the full-length ... -
+Open data
-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 | |||||||||
Components |
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Keywords | SIGNALING PROTEIN / receptor tyrosine kinases / epidermal growth factor receptor | |||||||||
Function / homology | Function and homology information negative regulation of secretion / positive regulation of hyaluronan biosynthetic process / negative regulation of cholesterol efflux / positive regulation of cerebellar granule cell precursor proliferation / cerebellar granule cell precursor proliferation / regulation of calcium ion import / positive regulation of protein localization to early endosome / regulation of protein localization to cell surface / positive regulation of epithelial tube formation / positive regulation of ubiquitin-dependent protein catabolic process ...negative regulation of secretion / positive regulation of hyaluronan biosynthetic process / negative regulation of cholesterol efflux / positive regulation of cerebellar granule cell precursor proliferation / cerebellar granule cell precursor proliferation / regulation of calcium ion import / positive regulation of protein localization to early endosome / regulation of protein localization to cell surface / positive regulation of epithelial tube formation / positive regulation of ubiquitin-dependent protein catabolic process / 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 / 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 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 / NFE2L2 regulating tumorigenic genes / 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 / branching morphogenesis of an epithelial tube / 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 / positive regulation of receptor internalization / regulation of JNK cascade / : / 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 / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of bone resorption / mammary gland alveolus development / GAB1 signalosome / positive regulation of DNA binding / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of phosphorylation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / ERK1 and ERK2 cascade / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / positive regulation of DNA repair / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / positive regulation of endothelial cell proliferation / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / regulation of ERK1 and ERK2 cascade / basal plasma membrane / guanyl-nucleotide exchange factor activity / neuron projection morphogenesis / positive regulation of mitotic nuclear division / positive regulation of endothelial cell migration / positive regulation of superoxide anion generation / platelet alpha granule lumen / positive regulation of peptidyl-threonine phosphorylation / positive regulation of DNA replication / Signal transduction by L1 Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 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 | 7syd.cif.gz | 354 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7syd.ent.gz | 271.6 KB | Display | PDB format |
PDBx/mmJSON format | 7syd.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/sy/7syd ftp://data.pdbj.org/pub/pdb/validation_reports/sy/7syd | HTTPS FTP |
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-Related structure data
Related structure data | 25522MC 7syeC 7sz0C 7sz1C 7sz5C 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 | Mass: 6229.027 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 |
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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:EGF complex / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES | ||||||||||||
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Molecular weight | Experimental value: NO | ||||||||||||
Source (natural) | Organism: Homo sapiens (human) | ||||||||||||
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 |
-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 / 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) |
-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 |