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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
Function / homology
Function and homology information


Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / mitotic nuclear division / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / positive regulation of trophectodermal cell proliferation / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex ...Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / mitotic nuclear division / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / positive regulation of trophectodermal cell proliferation / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex / : / proteoglycan biosynthetic process / negative regulation of cholangiocyte apoptotic process / positive regulation of glycoprotein biosynthetic process / myotube cell development / Extra-nuclear estrogen signaling / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / negative regulation of neuroinflammatory response / protein kinase complex / bone mineralization involved in bone maturation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / positive regulation of cell growth involved in cardiac muscle cell development / negative regulation of vascular associated smooth muscle cell apoptotic process / protein transporter activity / IRS-related events triggered by IGF1R / insulin-like growth factor binding / exocytic vesicle / negative regulation of muscle cell apoptotic process / positive regulation of meiotic cell cycle / positive regulation of DNA metabolic process / positive regulation of developmental growth / cell activation / positive regulation of calcineurin-NFAT signaling cascade / male sex determination / prostate gland epithelium morphogenesis / exocrine pancreas development / mammary gland development / insulin receptor complex / negative regulation of hepatocyte apoptotic process / positive regulation of transcription regulatory region DNA binding / insulin-like growth factor I binding / insulin receptor activity / transcytosis / alphav-beta3 integrin-IGF-1-IGF1R complex / positive regulation of kinase activity / positive regulation of Ras protein signal transduction / positive regulation of protein-containing complex disassembly / myoblast differentiation / positive regulation of insulin-like growth factor receptor signaling pathway / myoblast proliferation / muscle organ development / negative regulation of interleukin-1 beta production / dendritic spine maintenance / cellular response to insulin-like growth factor stimulus / response to L-glutamate / insulin binding / negative regulation of MAPK cascade / adrenal gland development / establishment of cell polarity / postsynaptic modulation of chemical synaptic transmission / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / positive regulation of activated T cell proliferation / positive regulation of smooth muscle cell migration / positive regulation of axon regeneration / amyloid-beta clearance / negative regulation of release of cytochrome c from mitochondria / positive regulation of osteoblast proliferation / positive regulation of cytokinesis / negative regulation of amyloid-beta formation / negative regulation of smooth muscle cell apoptotic process / phosphatidylinositol-mediated signaling / regulation of JNK cascade / negative regulation of tumor necrosis factor production / insulin receptor substrate binding / estrous cycle / positive regulation of glycogen biosynthetic process / G-protein alpha-subunit binding / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / epithelial to mesenchymal transition / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of DNA binding / SHC-related events triggered by IGF1R / positive regulation of osteoblast differentiation / phosphatidylinositol 3-kinase binding / peptidyl-tyrosine autophosphorylation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to transforming growth factor beta stimulus / cell surface receptor protein tyrosine kinase signaling pathway / T-tubule / positive regulation of glycolytic process / activation of protein kinase B activity / transmembrane receptor protein tyrosine kinase activity / protein serine/threonine kinase activator activity / positive regulation of mitotic nuclear division / cerebellum development
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/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like ...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/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 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-like growth factor I / 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 / Yu HT / Bai XC
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 23, 2019-
Current statusOct 23, 2019Processing 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
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  • 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
Voxel sizeX=Y=Z: 1.07 Å
Density
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)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Supramolecule #3: HsIGF1

SupramoleculeName: HsIGF1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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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

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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

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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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