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Yorodumi- PDB-6pxv: Cryo-EM structure of full-length insulin receptor bound to 4 insu... -
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-Basic information
Entry | Database: PDB / ID: 6pxv | ||||||
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Title | Cryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the extracellular region. | ||||||
Components |
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Keywords | SIGNALING PROTEIN/HORMONE / insulin receptor / insulin / SIGNALING PROTEIN-HORMONE complex | ||||||
Function / homology | Function and homology information regulation of female gonad development / positive regulation of meiotic cell cycle / positive regulation of developmental growth / insulin-like growth factor II binding / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly ...regulation of female gonad development / positive regulation of meiotic cell cycle / positive regulation of developmental growth / insulin-like growth factor II binding / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / cargo receptor activity / dendritic spine maintenance / insulin binding / PTB domain binding / adrenal gland development / neuronal cell body membrane / Signaling by Insulin receptor / IRS activation / activation of protein kinase activity / amyloid-beta clearance / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / transport across blood-brain barrier / insulin receptor substrate binding / positive regulation of glycogen biosynthetic process / epidermis development / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / dendrite membrane / Insulin receptor recycling / insulin-like growth factor receptor binding / neuron projection maintenance / positive regulation of glycolytic process / activation of protein kinase B activity / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / Insulin receptor signalling cascade / learning / caveola / positive regulation of glucose import / positive regulation of MAP kinase activity / receptor internalization / hormone activity / receptor protein-tyrosine kinase / memory / cellular response to growth factor stimulus / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / male gonad development / late endosome / insulin receptor signaling pathway / glucose homeostasis / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / positive regulation of MAPK cascade / protein autophosphorylation / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / positive regulation of cell migration / symbiont entry into host cell / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / protein domain specific binding / external side of plasma membrane / axon / protein phosphorylation / positive regulation of cell population proliferation / protein-containing complex binding / regulation of DNA-templated transcription / GTP binding / positive regulation of DNA-templated transcription / extracellular exosome / extracellular region / ATP binding / membrane / identical protein binding / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | ||||||
Authors | Uchikawa, E. / Choi, E. / Shang, G.J. / Yu, H.T. / Bai, X.C. | ||||||
Citation | Journal: Elife / Year: 2019 Title: Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex. Authors: Emiko Uchikawa / Eunhee Choi / Guijun Shang / Hongtao Yu / Xiao-Chen Bai / Abstract: Insulin signaling controls metabolic homeostasis. Here, we report the cryo-EM structure of full-length insulin receptor (IR) and insulin complex in the active state. This structure unexpectedly ...Insulin signaling controls metabolic homeostasis. Here, we report the cryo-EM structure of full-length insulin receptor (IR) and insulin complex in the active state. This structure unexpectedly reveals that maximally four insulins can bind the 'T'-shaped IR dimer at four distinct sites related by 2-fold symmetry. Insulins 1 and 1' bind to sites 1 and 1', formed by L1 of one IR protomer and α-CT and FnIII-1 of the other. Insulins 2 and 2' bind to sites 2 and 2' on FnIII-1 of each protomer. Mutagenesis and cellular assays show that both sites 1 and 2 are required for optimal insulin binding and IR activation. We further identify a homotypic FnIII-2-FnIII-2 interaction in mediating the dimerization of membrane proximal domains in the active IR dimer. Our results indicate that binding of multiple insulins at two distinct types of sites disrupts the autoinhibited apo-IR dimer and stabilizes the active dimer. | ||||||
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 | 6pxv.cif.gz | 444.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6pxv.ent.gz | 372.1 KB | Display | PDB format |
PDBx/mmJSON format | 6pxv.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/px/6pxv ftp://data.pdbj.org/pub/pdb/validation_reports/px/6pxv | HTTPS FTP |
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-Related structure data
Related structure data | 20522MC 6pxwC 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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1 |
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-Components
#1: Protein | Mass: 153913.312 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Homo sapiens (human) References: UniProt: P06213, receptor protein-tyrosine kinase #2: Protein | Mass: 8380.529 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Homo sapiens (human) / References: UniProt: A6XGL2 |
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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 insulin receptor/insulin complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 0.336 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 7 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: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % |
-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 / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 15 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 1161851 | ||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 235707 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL |