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- PDB-8eyr: Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutan... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8eyr | |||||||||
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Title | Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation | |||||||||
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![]() | SIGNALING PROTEIN / IGF1R / IGF1 | |||||||||
Function / homology | ![]() 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 smooth muscle cell migration / positive regulation of axon regeneration / positive regulation of activated T cell proliferation / 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 / SHC-related events triggered by IGF1R / positive regulation of DNA binding / 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 | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å | |||||||||
![]() | Li, J. / Wu, J.Y. / Hall, C. / Bai, X.C. / Choi, E. | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor. Authors: Jie Li / Jiayi Wu / Catherine Hall / Xiao-Chen Bai / Eunhee Choi / ![]() Abstract: The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked ...The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the -shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a -shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the -shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation. | |||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 325.9 KB | Display | ![]() |
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PDB format | ![]() | 255.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1.1 MB | Display | |
Data in XML | ![]() | 62.5 KB | Display | |
Data in CIF | ![]() | 91.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 28693MC ![]() 8eyxC ![]() 8eyyC ![]() 8ez0C M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 144481.953 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: Q60751, receptor protein-tyrosine kinase #2: Protein | Mass: 21881.320 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Conc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2600 nm / Nominal defocus min: 1600 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
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Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 1909017 | ||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21684 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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