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- EMDB-20524: Cryo-EM structure of full-length IGF1R-IGF1 complex. Only the ext... -

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Basic information

Entry
Database: EMDB / ID: EMD-20524
TitleCryo-EM structure of full-length IGF1R-IGF1 complex. Only the extracellular region of the complex is resolved.
Map datafull-length IGF1R-IGF1 complex
Sample
  • Complex: Full-length MmIGF1R-HsIGF1 complex
    • Complex: MmIGF1R
      • Protein or peptide: Insulin-like growth factor 1 receptor
    • Complex: HsIGF1
      • Protein or peptide: Insulin-like growth factor I
KeywordsIGF1R / IGF1 / SIGNALING PROTEIN-HORMONE complex
Function / homology
Function and homology information


negative regulation of cholangiocyte apoptotic process / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / positive regulation of steroid hormone biosynthetic process / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex ...negative regulation of cholangiocyte apoptotic process / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / positive regulation of steroid hormone biosynthetic process / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex / positive regulation of trophectodermal cell proliferation / negative regulation of muscle cell apoptotic process / prostate gland stromal morphogenesis / positive regulation of type B pancreatic cell proliferation / type II pneumocyte differentiation / neuronal dense core vesicle lumen / positive regulation of glycoprotein biosynthetic process / proteoglycan biosynthetic process / regulation of establishment or maintenance of cell polarity / chondroitin sulfate proteoglycan biosynthetic process / positive regulation of transcription regulatory region DNA binding / insulin-like growth factor receptor activity / myotube cell development / positive regulation of DNA metabolic process / protein kinase complex / Extra-nuclear estrogen signaling / negative regulation of neuroinflammatory response / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / bone mineralization involved in bone maturation / positive regulation of cell growth involved in cardiac muscle cell development / IRS-related events triggered by IGF1R / negative regulation of vascular associated smooth muscle cell apoptotic process / positive regulation of cerebellar granule cell precursor proliferation / protein transporter activity / lung vasculature development / exocytic vesicle / cerebellar granule cell precursor proliferation / positive regulation of myoblast proliferation / transcytosis / positive regulation of meiotic cell cycle / positive regulation of axon regeneration / lung lobe morphogenesis / positive regulation of myelination / cell activation / negative regulation of hepatocyte apoptotic process / glial cell differentiation / negative regulation of androgen receptor signaling pathway / positive regulation of developmental growth / prostate gland epithelium morphogenesis / positive regulation of calcineurin-NFAT signaling cascade / transmembrane receptor protein tyrosine kinase activator activity / prostate gland growth / male sex determination / insulin receptor complex / positive regulation of protein-containing complex disassembly / insulin-like growth factor I binding / type B pancreatic cell proliferation / insulin receptor activity / mammary gland development / exocrine pancreas development / alphav-beta3 integrin-IGF-1-IGF1R complex / myoblast differentiation / cell surface receptor signaling pathway via STAT / positive regulation of insulin-like growth factor receptor signaling pathway / regulation of nitric oxide biosynthetic process / positive regulation of Ras protein signal transduction / response to L-glutamate / dendritic spine maintenance / activation of protein kinase B activity / positive regulation of smooth muscle cell migration / regulation of JNK cascade / growth hormone receptor signaling pathway / insulin binding / positive regulation of DNA binding / adrenal gland development / negative regulation of interleukin-1 beta production / lung alveolus development / muscle organ development / cellular response to insulin-like growth factor stimulus / branching morphogenesis of an epithelial tube / androgen receptor signaling pathway / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / positive regulation of osteoblast proliferation / positive regulation of cardiac muscle hypertrophy / negative regulation of release of cytochrome c from mitochondria / positive regulation of cytokinesis / type I pneumocyte differentiation / establishment of cell polarity / negative regulation of amyloid-beta formation / inner ear development / negative regulation of smooth muscle cell apoptotic process / amyloid-beta clearance / myoblast proliferation / insulin receptor substrate binding / positive regulation of activated T cell proliferation / epithelial to mesenchymal transition / negative regulation of tumor necrosis factor production / Synthesis, secretion, and deacylation of Ghrelin
Similarity search - Function
Insulin-like growth factor I / Insulin-like growth factor / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site ...Insulin-like growth factor I / Insulin-like growth factor / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 / 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-like growth factor 1 / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesMus musculus (house mouse) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsLi J / Choi E
CitationJournal: Nat Commun / Year: 2019
Title: Structural basis of the activation of type 1 insulin-like growth factor receptor.
Authors: Jie Li / Eunhee Choi / Hongtao Yu / Xiao-Chen Bai /
Abstract: Type 1 insulin-like growth factor receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation, and can be activated by IGF1, IGF2, and insulin. Here, we report the ...Type 1 insulin-like growth factor receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation, and can be activated by IGF1, IGF2, and insulin. Here, we report the cryo-EM structure of full-length IGF1R-IGF1 complex in the active state. This structure reveals that only one IGF1 molecule binds the Γ-shaped asymmetric IGF1R dimer. The IGF1-binding site is formed by the L1 and CR domains of one IGF1R protomer and the α-CT and FnIII-1 domains of the other. The liganded α-CT forms a rigid beam-like structure with the unliganded α-CT, which hinders the conformational change of the unliganded α-CT required for binding of a second IGF1 molecule. We further identify an L1-FnIII-2 interaction that mediates the dimerization of membrane-proximal domains of IGF1R. This interaction is required for optimal receptor activation. Our study identifies a source of the negative cooperativity in IGF1 binding to IGF1R and reveals the structural basis of IGF1R activation.
History
DepositionJul 29, 2019-
Header (metadata) releaseOct 23, 2019-
Map releaseOct 23, 2019-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.018
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6pyh
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20524.png

Downloads & links

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Map

FileDownload / File: emd_20524.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfull-length IGF1R-IGF1 complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 280 pix.
= 299.6 Å		1.07 Å/pix.
x 280 pix.
= 299.6 Å		1.07 Å/pix.
x 280 pix.
= 299.6 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: 0.018 / Movie #1: 0.018
Minimum - Maximum-0.036028337 - 0.06711113
Average (Standard dev.)0.00027255915 (±0.0021795193)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 299.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z299.600299.600299.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0360.0670.000

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Supplemental data

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Sample components

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Entire : Full-length MmIGF1R-HsIGF1 complex

EntireName: Full-length MmIGF1R-HsIGF1 complex
Components
  • Complex: Full-length MmIGF1R-HsIGF1 complex
    • Complex: MmIGF1R
      • Protein or peptide: Insulin-like growth factor 1 receptor
    • Complex: HsIGF1
      • Protein or peptide: Insulin-like growth factor I

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Supramolecule #1: Full-length MmIGF1R-HsIGF1 complex

SupramoleculeName: Full-length MmIGF1R-HsIGF1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 336 KDa

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Supramolecule #2: MmIGF1R

SupramoleculeName: MmIGF1R / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #3: HsIGF1

SupramoleculeName: HsIGF1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Insulin-like growth factor 1 receptor

MacromoleculeName: Insulin-like growth factor 1 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 145.279906 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EICGPGIDIR NDYQQLKRLE NCTVIEGFLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTIDWSL ILDAVSNNYI VGNKPPKECG DLCPGTLEEK P MCEKTTIN ...String:
EICGPGIDIR NDYQQLKRLE NCTVIEGFLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTIDWSL ILDAVSNNYI VGNKPPKECG DLCPGTLEEK P MCEKTTIN NEYNYRCWTT NRCQKMCPSV CGKRACTENN ECCHPECLGS CHTPDDNTTC VACRHYYYKG VCVPACPPGT YR FEGWRCV DRDFCANIPN AESSDSDGFV IHDDECMQEC PSGFIRNSTQ SMYCIPCEGP CPKVCGDEEK KTKTIDSVTS AQM LQGCTI LKGNLLINIR RGNNIASELE NFMGLIEVVT GYVKIRHSHA LVSLSFLKNL RLILGEEQLE GNYSFYVLDN QNLQ QLWDW NHRNLTVRSG KMYFAFNPKL CVSEIYRMEE VTGTKGRQSK GDINTRNNGE RASCESDVLR FTSTTTWKNR IIITW HRYR PPDYRDLISF TVYYKEAPFK NVTEYDGQDA CGSNSWNMVD VDLPPNKEGE PGILLHGLKP WTQYAVYVKA VTLTMV END HIRGAKSEIL YIRTNASVPS IPLDVLSASN SSSQLIVKWN PPTLPNGNLS YYIVRWQRQP QDGYLYRHNY CSKDKIP IR KYADGTIDVE EVTENPKTEV CGGDKGPCCA CPKTEAEKQA EKEEAEYRKV FENFLHNSIF VPRPERRRRD VMQVANTT M SSRSRNTTVA DTYNITDPEE FETEYPFFES RVDNKERTVI SNLRPFTLYR IDIHSCNHEA EKLGCSASNF VFARTMPAE GADDIPGPVT WEPRPENSIF LKWPEPENPN GLILMYEIKY GSQVEDQREC VSRQEYRKYG GAKLNRLNPG NYTARIQATS LSGNGSWTD PVFFYVPAKT TYENFMHLII ALPVAILLIV GGLVIMLYVF HRKRNNSRLG NGVLYASVNP EAFSAADVYV P DEWEVARE KITMNRELGQ GSFGMVYEGV AKGVVKDEPE TRVAIKTVNE AASMRERIEF LNEASVMKEF NCHHVVRLLG VV SQGQPTL VIMELMTRGD LKSYLRSLRP EVEQNNLVLI PPSLSKMIQM AGEIADGMAY LNANKFVHRN LAARNCMVAE DFT VKIGDF GMTRDIYETD YYRKGGKGLL PVRWMSPESL KDGVFTTHSD VWSFGVVLWE IATLAEQPYQ GLSNEQVLRF VMEG GLLDK PDNCPDMLFE LMRMCWQYNP KMRPSFLEII GSIKDEMEPS FQEVSFYYSE ENKPPEPGTS SGLEVLFQ

UniProtKB: Insulin-like growth factor 1 receptor

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Macromolecule #2: Insulin-like growth factor I

MacromoleculeName: Insulin-like growth factor I / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.663752 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GPETLCGAEL VDALQFVCGD RGFYFNKPTG YGSSSRRAPQ TGIVDECCFR SCDLRRLEMY CAPLKPAKSA

UniProtKB: Insulin-like growth factor 1

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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: 1431211
Startup modelType of model: OTHER / Details: We used RELION to generate the initial model.
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 51573
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-6pyh:
Cryo-EM structure of full-length IGF1R-IGF1 complex. Only the extracellular region of the complex is resolved.

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