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- PDB-6ce7: Insulin Receptor ectodomain in complex with one insulin molecule -

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Basic information

Entry
Database: PDB / ID: 6ce7
TitleInsulin Receptor ectodomain in complex with one insulin molecule
Components
  • Insulin A chain
  • Insulin B chain
  • Insulin receptor
  • Insulin receptor subunit alpha
KeywordsSIGNALING 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 / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly ...cellular response to palmitoleic acid / response to L-arginine / regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / insulin receptor activity / exocrine pancreas development / dendritic spine maintenance / cargo receptor activity / insulin binding / adrenal gland development / neuronal cell body membrane / PTB domain binding / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / regulation of protein secretion / Insulin processing / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / amyloid-beta clearance / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / positive regulation of receptor internalization / regulation of embryonic development / insulin receptor substrate binding / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / protein kinase activator activity / epidermis development / activation of protein kinase B activity / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of insulin receptor signaling pathway / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / heart morphogenesis / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / transport across blood-brain barrier / regulation of protein localization to plasma membrane / phosphatidylinositol 3-kinase binding / nitric oxide-cGMP-mediated signaling / transport vesicle / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / Insulin receptor recycling / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / dendrite membrane / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / positive regulation of glycolytic process / positive regulation of cytokine production / endosome lumen / positive regulation of long-term synaptic potentiation / acute-phase response / positive regulation of protein secretion / positive regulation of D-glucose import / learning / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / wound healing / positive regulation of neuron projection development / receptor protein-tyrosine kinase / hormone activity / negative regulation of protein catabolic process / regulation of synaptic plasticity / caveola / cellular response to growth factor stimulus / receptor internalization / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / cognition / memory / male gonad development / glucose metabolic process / cellular response to insulin stimulus / positive regulation of nitric oxide biosynthetic process / insulin receptor signaling pathway
Similarity search - Function
Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. ...Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Fibronectin type III domain / Growth factor receptor cysteine-rich domain superfamily / : / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Insulin / Insulin / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Ovis aries (sheep)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.4 Å
AuthorsScapin, G. / Dandey, V.P. / Zhang, Z. / Strickland, C. / Potter, C.S. / Carragher, B.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
National Institutes of Health/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD)OD019994 United States
Simons Foundation349247 United States
CitationJournal: 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
DepositionFeb 11, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 14, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2018Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Apr 18, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Other / Category: atom_sites / cell / pdbx_audit_support
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB / _pdbx_audit_support.funding_organization
Revision 1.4Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
B: Insulin receptor
A: Insulin receptor
N: Insulin A chain
O: Insulin B chain
P: Insulin receptor subunit alpha


Theoretical massNumber of molelcules
Total (without water)221,3115
Polymers221,3115
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5710 Å2
ΔGint-31 kcal/mol
Surface area66140 Å2

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Components

#1: Protein Insulin receptor / IR


Mass: 105926.094 Da / Num. of mol.: 2 / Fragment: residues 28-956
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
#2: Protein/peptide Insulin A chain


Mass: 2383.698 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308
#3: Protein/peptide Insulin B chain


Mass: 3403.927 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Ovis aries (sheep) / References: UniProt: P01318
#4: Protein/peptide Insulin receptor subunit alpha / IR


Mass: 3671.163 Da / Num. of mol.: 1 / 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
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Insulin Receptor Ectodomain in complex with one insulin moleculeCOMPLEXall0MULTIPLE SOURCES
2Insulin receptorCOMPLEX#11RECOMBINANT
3Insulin A chainCOMPLEX#21RECOMBINANT
4Insulin B chainCOMPLEX#31RECOMBINANT
5Insulin receptor subunit alphaCOMPLEX#41RECOMBINANT
Molecular weightValue: 0.215 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Ovis aries (sheep)9940
45Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Mus musculus (house mouse)10090
25Mus musculus (house mouse)10090
Buffer solutionpH: 7.5 / Details: Hepes Saline (HBS)
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 293 K / Details: Grids made with SpotItOn

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 45.5 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.12_2829: / Classification: refinement
EM software
IDNameVersionCategory
4GctfCTF correction
7Cootmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARC0.6.5classification
12cryoSPARC0.6.53D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 7.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 48315 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00710522
ELECTRON MICROSCOPYf_angle_d1.09714258
ELECTRON MICROSCOPYf_dihedral_angle_d7.4266300
ELECTRON MICROSCOPYf_chiral_restr0.0591552
ELECTRON MICROSCOPYf_plane_restr0.0071831

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