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- EMDB-20522: Cryo-EM structure of full-length insulin receptor bound to 4 insu... -

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Basic information

Entry
Database: EMDB / ID: EMD-20522
TitleCryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the extracellular region.
Map dataCryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the entire extracellular region.
Sample
  • Complex: Full-length insulin receptor/insulin complex
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin
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 / neuronal cell body membrane / adrenal gland development / Signaling by Insulin receptor / IRS activation / amyloid-beta clearance / activation of protein kinase activity / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / transport across blood-brain barrier / insulin receptor substrate binding / epidermis development / positive regulation of glycogen biosynthetic process / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / dendrite membrane / Insulin receptor recycling / insulin-like growth factor receptor binding / receptor-mediated endocytosis / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / learning / caveola / positive regulation of glucose import / positive regulation of MAP kinase activity / hormone activity / receptor internalization / receptor protein-tyrosine kinase / memory / cellular response to growth factor stimulus / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / male gonad development / cell surface receptor protein tyrosine kinase signaling pathway / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / late endosome / glucose homeostasis / insulin receptor signaling pathway / 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 / carbohydrate metabolic process / positive regulation of cell migration / positive regulation of protein phosphorylation / symbiont entry into host cell / G protein-coupled receptor signaling pathway / axon / protein domain specific binding / external side of plasma membrane / protein phosphorylation / positive regulation of cell population proliferation / protein-containing complex binding / GTP binding / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / extracellular exosome / extracellular region / ATP binding / membrane / identical protein binding / plasma membrane
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/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. ...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/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / 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 III domain / 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 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsUchikawa E / Choi E / Shang GJ / Yu HT / Bai XC
CitationJournal: 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
DepositionJul 27, 2019-
Header (metadata) releaseSep 4, 2019-
Map releaseSep 4, 2019-
UpdateSep 4, 2019-
Current statusSep 4, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.036
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.036
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6pxv
  • Surface level: 0.036
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20522.png

Downloads & links

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Map

FileDownload / File: emd_20522.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the entire extracellular region.
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.036 / Movie #1: 0.036
Minimum - Maximum-0.054458052 - 0.121365845
Average (Standard dev.)0.00043268374 (±0.0043145735)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 321.00003 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z321.000321.000321.000
α/β/γ90.00090.00090.000
start NX/NY/NZ-39-149-104
NX/NY/NZ201201211
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0540.1210.000

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Supplemental data

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Sample components

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Entire : Full-length insulin receptor/insulin complex

EntireName: Full-length insulin receptor/insulin complex
Components
  • Complex: Full-length insulin receptor/insulin complex
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin

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Supramolecule #1: Full-length insulin receptor/insulin complex

SupramoleculeName: Full-length insulin receptor/insulin complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 336 KDa

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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: 153.913312 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDIC P GTAKGKTN ...String:
HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK 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 DVPSNIAKII IGPLIFVFLF SVVIGSIYLF LRKRQPDGPL GPLYASSNPE F LTASDVFP CSVYVPDEWE VSREKITLLR ELGQGSFGMV YEGNARDIIK GEAETRVAVK TVNESASLRE RIEFLNEASV MK GFTCHHV VRLLGVVSKG QPTLVVMELM AHGDLKSYLR SLRPEAENNP GRPPPTLQEM IQMAAEIADG MAYLNAKKFV HRN LAARNC MVAHDFTVKI GDFGMTRDIY ETDYYRKGGK GLLPVRWMAP ESLKDGVFTT SSDMWSFGVV LWEITSLAEQ PYQG LSNEQ VLKFVMDGGY LDQPDNCPER VTDLMRMCWQ FNPKMRPTFL EIVNLLKDDL HPSFPEVSFF HSEENKAPES EELEM EFED MENVPLDRSS HCQREEAGGR DGGSSLGFKR SYEEHIPYTH MNGGKKNGAA ATAPRSNPSL ESSGLEVLFQ

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Macromolecule #2: Insulin

MacromoleculeName: Insulin / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.380529 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
FVNQHLCGSH LVEALYLVCG ERGFFYTPKT RREAEDLQGS LQPLALEGSL QKRGIVEQCC TSICSLYQLE NYCN

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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

Concentration7 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 IS (4k x 4k) / Average exposure time: 15.0 sec. / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1161851
Startup modelType of model: OTHER / Details: We used RELION to generate the initial model.
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final 3D classificationNumber classes: 8 / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 235707

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6pxv:
Cryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the extracellular region.

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