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Yorodumi- PDB-6ce9: Insulin Receptor ectodomain in complex with two insulin molecules -
+Open data
-Basic information
Entry | Database: PDB / ID: 6ce9 | ||||||||||||
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Title | Insulin Receptor ectodomain in complex with two insulin molecules | ||||||||||||
Components |
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Keywords | SIGNALING PROTEIN / signaling | ||||||||||||
Function / homology | Function and homology information cellular response to palmitoleic acid / response to L-arginine / 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 ...cellular response to palmitoleic acid / response to L-arginine / 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 / negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / PTB domain binding / adrenal gland development / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / activation of protein kinase activity / IRS activation / Insulin processing / neuronal cell body membrane / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / positive regulation of receptor internalization / amyloid-beta clearance / alpha-beta T cell activation / transport across blood-brain barrier / regulation of embryonic development / regulation of amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / insulin receptor substrate binding / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / epidermis development / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / negative regulation of gluconeogenesis / Signal attenuation / negative regulation of lipid catabolic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of lipid biosynthetic process / positive regulation of insulin receptor signaling pathway / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / nitric oxide-cGMP-mediated signaling / positive regulation of protein autophosphorylation / transport vesicle / insulin-like growth factor receptor binding / Insulin receptor recycling / dendrite membrane / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / positive regulation of nitric-oxide synthase activity / learning / acute-phase response / positive regulation of cytokine production / cognition / positive regulation of long-term synaptic potentiation / Regulation of insulin secretion / endosome lumen / positive regulation of D-glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin receptor binding / wound healing / positive regulation of MAP kinase activity / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / hormone activity / caveola / regulation of synaptic plasticity / receptor internalization / cellular response to growth factor stimulus / positive regulation of neuron projection development / memory / positive regulation of protein localization to nucleus Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) Ovis aries (sheep) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å | ||||||||||||
Authors | Scapin, G. / Dandey, V.P. / Zhang, Z. / Strickland, C. / Potter, C.S. / Carragher, B. | ||||||||||||
Funding support | United States, 3items
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Citation | Journal: Nature / Year: 2018 Title: Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis. Authors: Giovanna Scapin / Venkata P Dandey / Zhening Zhang / Winifred Prosise / Alan Hruza / Theresa Kelly / Todd Mayhood / Corey Strickland / Clinton S Potter / Bridget Carragher / Abstract: The insulin receptor is a dimeric protein that has a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter ...The insulin receptor is a dimeric protein that has a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter levels. Insulin receptor dysfunction has been associated with many diseases, including diabetes, cancer and Alzheimer's disease. The primary sequence of the receptor has been known since the 1980s, and is composed of an extracellular portion (the ectodomain, ECD), a single transmembrane helix and an intracellular tyrosine kinase domain. Binding of insulin to the dimeric ECD triggers auto-phosphorylation of the tyrosine kinase domain and subsequent activation of downstream signalling molecules. Biochemical and mutagenesis data have identified two putative insulin-binding sites, S1 and S2. The structures of insulin bound to an ECD fragment containing S1 and of the apo ectodomain have previously been reported, but details of insulin binding to the full receptor and the signal propagation mechanism are still not understood. Here we report single-particle cryo-electron microscopy reconstructions of the 1:2 (4.3 Å) and 1:1 (7.4 Å) complexes of the insulin receptor ECD dimer with insulin. The symmetrical 4.3 Å structure shows two insulin molecules per dimer, each bound between the leucine-rich subdomain L1 of one monomer and the first fibronectin-like domain (FnIII-1) of the other monomer, and making extensive interactions with the α-subunit C-terminal helix (α-CT helix). The 7.4 Å structure has only one similarly bound insulin per receptor dimer. The structures confirm the binding interactions at S1 and define the full S2 binding site. These insulin receptor states suggest that recruitment of the α-CT helix upon binding of the first insulin changes the relative subdomain orientations and triggers downstream signal propagation. | ||||||||||||
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 | 6ce9.cif.gz | 257.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6ce9.ent.gz | 205.2 KB | Display | PDB format |
PDBx/mmJSON format | 6ce9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6ce9_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 6ce9_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 6ce9_validation.xml.gz | 46.9 KB | Display | |
Data in CIF | 6ce9_validation.cif.gz | 70.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ce/6ce9 ftp://data.pdbj.org/pub/pdb/validation_reports/ce/6ce9 | HTTPS FTP |
-Related structure data
Related structure data | 7462MC 7461C 7463C 6ce7C 6cebC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 1 types, 2 molecules AB
#1: Protein | Mass: 104736.844 Da / Num. of mol.: 2 / Fragment: Ectodomain residues 28-944 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Mus musculus (house mouse) References: UniProt: P06213, receptor protein-tyrosine kinase |
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-Protein/peptide , 3 types, 6 molecules MPKNLO
#2: Protein/peptide | Mass: 3671.163 Da / Num. of mol.: 2 / Fragment: residues 718-747 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Mus musculus (house mouse) References: UniProt: P06213, receptor protein-tyrosine kinase #3: Protein/peptide | Mass: 2383.698 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308 #4: Protein/peptide | Mass: 3403.927 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Ovis aries (sheep) / References: UniProt: P01318 |
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-Sugars , 5 types, 14 molecules
#5: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #6: Polysaccharide | Source method: isolated from a genetically manipulated source #7: Polysaccharide | Source method: isolated from a genetically manipulated source #8: Polysaccharide | Source method: isolated from a genetically manipulated source #9: Sugar | ChemComp-NAG / |
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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 |
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Molecular weight | Value: 0.215 MDa / Experimental value: NO | ||||||||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.5 / Details: Hepes Saline (HBS) | ||||||||||||||||||||||||||||||||||||
Specimen | Conc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||||||||
Vitrification | Instrument: HOMEMADE PLUNGER / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 293 K / Details: Grids made with SpotItOn |
-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: OTHER |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 45.5 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.12_2829: / Classification: refinement | ||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 147436 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT | ||||||||||||||||||||||||||||||||
Refine LS restraints |
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