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- EMDB-7462: Insulin Receptor ectodomain in complex with two insulin molecules -

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Basic information

Entry
Database: EMDB / ID: EMD-7462
TitleInsulin Receptor ectodomain in complex with two insulin molecules
Map dataInsulin Receptor ectodomain in complex with two insulin molecules
Sample
  • Complex: Insulin Receptor Ectodomain in complex with two insulin molecules
    • Complex: Insulin receptor
      • Protein or peptide: Insulin receptor
    • Complex: Insulin receptor subunit alpha
      • Protein or peptide: Insulin receptor
    • Complex: Insulin A chain
      • Protein or peptide: Insulin A chain
    • Complex: Insulin B chain
      • Protein or peptide: Insulin B chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordssignaling / SIGNALING PROTEIN
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 / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / 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 / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / dendritic spine maintenance / insulin binding / negative regulation of glycogen catabolic process / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / PTB domain binding / IRS activation / cargo receptor activity / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / positive regulation of peptide hormone secretion / negative regulation of acute inflammatory response / neuronal cell body membrane / positive regulation of respiratory burst / Regulation of gene expression in beta cells / relaxation of vascular associated smooth muscle / alpha-beta T cell activation / amyloid-beta clearance / acute-phase response / heart morphogenesis / positive regulation of receptor internalization / Synthesis, secretion, and deacylation of Ghrelin / insulin receptor substrate binding / negative regulation of gluconeogenesis / fatty acid homeostasis / negative regulation of protein secretion / positive regulation of brown fat cell differentiation / positive regulation of dendritic spine maintenance / positive regulation of insulin receptor signaling pathway / positive regulation of glycogen biosynthetic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / protein kinase activator activity / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of respiratory burst involved in inflammatory response / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / nitric oxide-cGMP-mediated signaling / regulation of protein localization to plasma membrane / phosphatidylinositol 3-kinase binding / Insulin receptor recycling / transport across blood-brain barrier / COPI-mediated anterograde transport / transport vesicle / positive regulation of nitric-oxide synthase activity / negative regulation of reactive oxygen species biosynthetic process / NPAS4 regulates expression of target genes / insulin-like growth factor receptor binding / positive regulation of D-glucose import across plasma membrane / positive regulation of mitotic nuclear division / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis / male gonad development / hormone activity / positive regulation of glycolytic process / regulation of embryonic development / Insulin receptor signalling cascade / learning / endosome lumen / dendrite membrane / positive regulation of protein secretion / wound healing / insulin receptor binding / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / positive regulation of neuron projection development / positive regulation of cell differentiation / negative regulation of protein catabolic process / Regulation of insulin secretion / memory / receptor protein-tyrosine kinase / vasodilation / positive regulation of protein localization to nucleus / regulation of synaptic plasticity / caveola / Golgi lumen / cognition / insulin receptor signaling pathway / positive regulation of nitric oxide biosynthetic process / cellular response to insulin stimulus / glucose homeostasis / late endosome / cell-cell signaling / protein autophosphorylation / positive regulation of cell growth / amyloid-beta binding / regulation of protein localization
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 / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsScapin G / Dandey VP
Funding support United States, 3 items
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, 2018-
Header (metadata) releaseFeb 28, 2018-
Map releaseMar 14, 2018-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.57
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.57
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6ce9
  • Surface level: 0.57
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7462.png

Downloads & links

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Map

FileDownload / File: emd_7462.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationInsulin Receptor ectodomain in complex with two insulin molecules
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 288 pix.
= 316.8 Å		1.1 Å/pix.
x 288 pix.
= 316.8 Å		1.1 Å/pix.
x 288 pix.
= 316.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.57 / Movie #1: 0.57
Minimum - Maximum-0.736299 - 1.8869687
Average (Standard dev.)0.0030915765 (±0.059577316)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 316.80002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z316.800316.800316.800
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-0.7361.8870.003

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Supplemental data

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Sample components

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Entire : Insulin Receptor Ectodomain in complex with two insulin molecules

EntireName: Insulin Receptor Ectodomain in complex with two insulin molecules
Components
  • Complex: Insulin Receptor Ectodomain in complex with two insulin molecules
    • Complex: Insulin receptor
      • Protein or peptide: Insulin receptor
    • Complex: Insulin receptor subunit alpha
      • Protein or peptide: Insulin receptor
    • Complex: Insulin A chain
      • Protein or peptide: Insulin A chain
    • Complex: Insulin B chain
      • Protein or peptide: Insulin B chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Insulin Receptor Ectodomain in complex with two insulin molecules

SupramoleculeName: Insulin Receptor Ectodomain in complex with two insulin molecules
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Molecular weightTheoretical: 215 KDa

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Supramolecule #2: Insulin receptor

SupramoleculeName: Insulin receptor / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Insulin receptor subunit alpha

SupramoleculeName: Insulin receptor subunit alpha / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Insulin A chain

SupramoleculeName: Insulin A chain / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #5: Insulin B chain

SupramoleculeName: Insulin B chain / type: complex / ID: 5 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Ovis aries (sheep)

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Macromolecule #1: Insulin receptor

MacromoleculeName: Insulin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 104.736844 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNHIVLNK DDNEECGDIC P GTAKGKTN ...String:
HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNHIVLNK DDNEECGDIC P GTAKGKTN CPATVINGQF VERCWTHSHC QKVCPTICKS HGCTAEGLCC HSECLGNCSQ PDDPTKCVAC RNFYLDGRCV ET CPPPYYH FQDWRCVNFS FCQDLHHKCK NSRRQGCHQY VIHNNKCIPE CPSGYTMNSS NLLCTPCLGP CPKVCHLLEG EKT IDSVTS AQELRGCTVI NGSLIINIRG GNNLAAELEA NLGLIEEISG YLKIRRSYAL VSLSFFRKLR LIRGETLEIG NYSF YALDN QNLRQLWDWS KHNLTITQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDQ ASCENELLKF SYIRT SFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN VTEFDGQDAC GSNSWTVVDI DPPLRSNDPK SQNHPGWLMR GLKPWT QYA IFVKTLVTFS DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSE LF ELDYCLKGLK LPSRTWSPPF ESEDSQKHNQ SEYEDSAGEC CSCPKTDSQI LKELEESSFR KTFEDYLHNV VFVPRPSR K RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAY VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRIRAT SLAGNGSWTE PTYFYVTDYL DVPSNIAK

UniProtKB: Insulin receptor

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Macromolecule #2: Insulin receptor

MacromoleculeName: Insulin receptor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.671163 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
QILKELEESS FRKTFEDYLH NVVFVPRPSR

UniProtKB: Insulin receptor

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Macromolecule #3: Insulin A chain

MacromoleculeName: Insulin A chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.383698 KDa
SequenceString:
GIVEQCCTSI CSLYQLENYC N

UniProtKB: Insulin

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Macromolecule #4: Insulin B chain

MacromoleculeName: Insulin B chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 3.403927 KDa
SequenceString:
FVNQHLCGSH LVEALYLVCG ERGFFYTPKA

UniProtKB: Insulin

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.3 mg/mL
BufferpH: 7.5 / Details: Hepes Saline (HBS)
VitrificationCryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 293 K / Instrument: HOMEMADE PLUNGER / Details: Grids made with SpotItOn.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 45.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 0.6.5) / Number images used: 147436
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC
Final angle assignmentType: OTHER / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-6ce9:
Insulin Receptor ectodomain in complex with two insulin molecules

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