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- PDB-8vjb: Cryo-EM structure of short form insulin receptor (IR-A) with four... -
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Basic information
Entry | Database: PDB / ID: 8vjb | ||||||
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Title | Cryo-EM structure of short form insulin receptor (IR-A) with four IGF2 bound, symmetric conformation. | ||||||
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![]() | SIGNALING PROTEIN / Insulin receptor / IGF2 / RTK | ||||||
Function / homology | ![]() spongiotrophoblast cell proliferation / negative regulation of muscle cell differentiation / positive regulation of skeletal muscle tissue growth / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / genomic imprinting / regulation of female gonad development / positive regulation of meiotic cell cycle ...spongiotrophoblast cell proliferation / negative regulation of muscle cell differentiation / positive regulation of skeletal muscle tissue growth / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / genomic imprinting / regulation of female gonad development / positive regulation of meiotic cell cycle / positive regulation of organ growth / 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 multicellular organism growth / positive regulation of protein-containing complex disassembly / cargo receptor activity / positive regulation of vascular endothelial cell proliferation / dendritic spine maintenance / insulin binding / PTB domain binding / adrenal gland development / Signaling by Insulin receptor / IRS activation / activation of protein kinase activity / transmembrane receptor protein tyrosine kinase activator activity / neuronal cell body membrane / amyloid-beta clearance / positive regulation of activated T cell proliferation / positive regulation of respiratory burst / positive regulation of receptor internalization / regulation of embryonic development / positive regulation of cell division / insulin receptor substrate binding / transport across blood-brain barrier / positive regulation of glycogen biosynthetic process / embryonic placenta development / epidermis development / SHC-related events triggered by IGF1R / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of insulin receptor signaling pathway / striated muscle cell differentiation / 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 / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / protein serine/threonine kinase activator activity / receptor-mediated endocytosis / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / learning / caveola / positive regulation of glucose import / animal organ morphogenesis / positive regulation of MAP kinase activity / insulin receptor binding / growth factor activity / hormone activity / receptor protein-tyrosine kinase / receptor internalization / memory / cellular response to growth factor stimulus / peptidyl-tyrosine phosphorylation / osteoblast differentiation / cellular response to insulin stimulus / glucose metabolic process / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / male gonad development / positive regulation of nitric oxide biosynthetic process / integrin binding / late endosome / Platelet degranulation / insulin receptor signaling pathway / glucose homeostasis / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / lysosome / receptor ligand activity / endosome membrane / positive regulation of cell migration / symbiont entry into host cell / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / protein domain specific binding Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å | ||||||
![]() | An, W. / Hall, C. / Li, J. / Huang, A. / Wu, J. / Park, J. / Bai, X.C. / Choi, E. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Activation of the insulin receptor by insulin-like growth factor 2. Authors: Weidong An / Catherine Hall / Jie Li / Albert Hung / Jiayi Wu / Junhee Park / Liwei Wang / Xiao-Chen Bai / Eunhee Choi / ![]() Abstract: Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular ...Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 392.6 KB | Display | ![]() |
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PDB format | ![]() | 299.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 43279MC ![]() 8u4bC ![]() 8u4cC ![]() 8u4eC ![]() 8vjcC C: citing same article ( M: map data used to model this data |
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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: 155329.094 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P06213, receptor protein-tyrosine kinase #2: Protein | Mass: 20170.398 Da / Num. of mol.: 4 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: Short form insulin receptor (IR-A) with four IGF2 bound, 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: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
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 / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
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
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 3422813 | ||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 66937 / Symmetry type: POINT | ||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL |