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- PDB-6pyh: Cryo-EM structure of full-length IGF1R-IGF1 complex. Only the ext... -

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Basic information

Entry
Database: PDB / ID: 6pyh
TitleCryo-EM structure of full-length IGF1R-IGF1 complex. Only the extracellular region of the complex is resolved.
Components
  • Insulin-like growth factor 1 receptor
  • Insulin-like growth factor IInsulin-like growth factor 1
KeywordsSIGNALING PROTEIN/HORMONE / IGF1R / IGF1 / SIGNALING PROTEIN-HORMONE complex
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 / negative regulation of neuroinflammatory response / positive regulation of steroid hormone biosynthetic process / protein kinase complex / positive regulation of cell growth involved in cardiac muscle cell development / negative regulation of vascular associated smooth muscle cell apoptotic process / protein transporter activity / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / bone mineralization involved in bone maturation / IRS-related events triggered by IGF1R / insulin-like growth factor binding / exocytic vesicle / negative regulation of muscle cell apoptotic process / negative regulation of smooth 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 / insulin-like growth factor I binding / positive regulation of transcription regulatory region DNA binding / insulin receptor activity / transcytosis / alphav-beta3 integrin-IGF-1-IGF1R complex / phosphatidylinositol-mediated signaling / positive regulation of kinase activity / positive regulation of Ras protein signal transduction / positive regulation of protein-containing complex disassembly / myoblast differentiation / myoblast proliferation / positive regulation of insulin-like growth factor receptor signaling pathway / muscle organ development / cellular response to insulin-like growth factor stimulus / response to L-glutamate / negative regulation of interleukin-1 beta production / dendritic spine maintenance / insulin binding / adrenal gland development / establishment of cell polarity / postsynaptic modulation of chemical synaptic transmission / negative regulation of amyloid-beta formation / negative regulation of MAPK cascade / positive regulation of activated T cell proliferation / protein tyrosine kinase activator activity / positive regulation of axon regeneration / positive regulation of cardiac muscle hypertrophy / positive regulation of smooth muscle cell migration / amyloid-beta clearance / negative regulation of release of cytochrome c from mitochondria / positive regulation of cytokinesis / positive regulation of osteoblast proliferation / regulation of JNK cascade / estrous cycle / negative regulation of tumor necrosis factor production / insulin receptor substrate binding / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G-protein alpha-subunit binding / epithelial to mesenchymal transition / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / positive regulation of glycogen biosynthetic process / positive regulation of DNA binding / positive regulation of osteoblast differentiation / SHC-related events triggered by IGF1R / 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 / T-tubule / insulin-like growth factor receptor binding / activation of protein kinase B activity / cerebellum development / transmembrane receptor protein tyrosine kinase activity / positive regulation of glycolytic process / protein serine/threonine kinase activator activity / axonogenesis
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsLi, J. / Choi, E. / Yu, H.T. / Bai, X.C.
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, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Insulin-like growth factor 1 receptor
B: Insulin-like growth factor I
D: Insulin-like growth factor 1 receptor


Theoretical massNumber of molelcules
Total (without water)298,2243
Polymers298,2243
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area7370 Å2
ΔGint-41 kcal/mol
Surface area85950 Å2

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Components

#1: Protein Insulin-like growth factor 1 receptor / / Insulin-like growth factor I receptor / IGF-I receptor


Mass: 145279.906 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Igf1r / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q60751, receptor protein-tyrosine kinase
#2: Protein Insulin-like growth factor I / Insulin-like growth factor 1 / IGF-I / Mechano growth factor / MGF / Somatomedin-C


Mass: 7663.752 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGF1, IBP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P05019

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Full-length MmIGF1R-HsIGF1 complexCOMPLEXall0RECOMBINANT
2MmIGF1RCOMPLEX#11RECOMBINANT
3HsIGF1COMPLEX#21RECOMBINANT
Molecular weightValue: 0.336 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Mus musculus (house mouse)10090
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
12Homo sapiens (human)9606HEK293
23Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenConc.: 7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 15 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameCategory
1RELIONparticle selection
2EPUimage acquisition
7Cootmodel fitting
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1431211
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 51573 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00713492
ELECTRON MICROSCOPYf_angle_d0.79918293
ELECTRON MICROSCOPYf_dihedral_angle_d6.9458090
ELECTRON MICROSCOPYf_chiral_restr0.051978
ELECTRON MICROSCOPYf_plane_restr0.0052372

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