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- EMDB-20523: Cryo-EM structure of full-length insulin receptor bound to 4 insu... -

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Basic information

Entry
Database: EMDB / ID: EMD-20523
TitleCryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the top part of the receptor complex.
Map dataCryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the top part of the complex
Sample
  • Complex: Full-length insulin receptor/insulin complex
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin
Function / homology
Function and homology information


cellular response to oxygen-containing compound / 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 / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity ...cellular response to oxygen-containing compound / 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 / 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 / activation of protein kinase activity / Signaling by Insulin receptor / IRS activation / neuronal cell body membrane / positive regulation of respiratory burst / positive regulation of receptor internalization / amyloid-beta clearance / regulation of embryonic development / insulin receptor substrate binding / transport across blood-brain barrier / positive regulation of glycogen biosynthetic process / epidermis development / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / Insulin receptor recycling / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / learning / positive regulation of D-glucose import / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / caveola / cellular response to growth factor stimulus / receptor internalization / hormone activity / memory / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / male gonad development / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / late endosome / insulin receptor signaling pathway / glucose homeostasis / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein autophosphorylation / positive regulation of MAPK cascade / 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 phosphorylation / protein domain specific binding / axon / external side of plasma membrane / positive regulation of cell population proliferation / regulation of DNA-templated transcription / protein-containing complex binding / GTP binding / positive regulation of DNA-templated transcription / extracellular exosome / extracellular region / ATP binding / identical protein binding / membrane / 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-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 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 / 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 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 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 28, 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: 0.055
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.055
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6pxw
  • Surface level: 0.055
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20523.png

Downloads & links

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Map

FileDownload / File: emd_20523.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 top part of the complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.055 / Movie #1: 0.055
Minimum - Maximum-0.12414066 - 0.2527832
Average (Standard dev.)0.00039242828 (±0.0054611587)
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-0.1240.2530.000

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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
GridDetails: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 IS (4k x 4k) / Average exposure time: 15.0 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
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.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 235707
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final 3D classificationNumber classes: 8 / Software - Name: RELION

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6pxw:
Cryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the top part of the receptor complex.

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