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- PDB-8dtm: Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 -
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Open data
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Basic information
Entry | Database: PDB / ID: 8dtm | ||||||
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Title | Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 | ||||||
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![]() | SIGNALING PROTEIN | ||||||
Function / homology | ![]() Signaling by Insulin receptor / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / regulation of female gonad development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth ...Signaling by Insulin receptor / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / regulation of female gonad development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / insulin receptor complex / exocrine pancreas development / insulin-like growth factor I binding / nuclear lumen / insulin binding / PTB domain binding / adrenal gland development / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / protein kinase activator activity / insulin receptor substrate binding / epidermis development / positive regulation of glycogen biosynthetic process / phosphatidylinositol 3-kinase binding / heart morphogenesis / insulin-like growth factor receptor binding / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / platelet-derived growth factor beta-receptor activity / fibroblast growth factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / insulin-like growth factor receptor activity / positive regulation of mitotic nuclear division / hepatocyte growth factor receptor activity / positive regulation of glycolytic process / animal organ morphogenesis / positive regulation of D-glucose import / epidermal growth factor receptor activity / cellular response to growth factor stimulus / receptor protein-tyrosine kinase / caveola / receptor internalization / recycling endosome membrane / male gonad development / positive regulation of nitric oxide biosynthetic process / nuclear envelope / late endosome / glucose homeostasis / insulin receptor signaling pathway / histone H2AXY142 kinase activity / histone H3Y41 kinase activity / amyloid-beta binding / protein tyrosine kinase activity / protein autophosphorylation / positive regulation of MAPK cascade / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of cell migration / G protein-coupled receptor signaling pathway / symbiont entry into host cell / positive regulation of cell population proliferation / protein-containing complex binding / GTP binding / positive regulation of DNA-templated transcription / ATP binding / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | ![]() ![]() synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å | ||||||
![]() | Park, J. / Li, J. / Mayer, J.P. / Ball, K.A. / Wu, J.Y. / Hall, C. / Accili, D. / Stowell, M.H.B. / Bai, X.C. / Choi, E. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Activation of the insulin receptor by an insulin mimetic peptide. Authors: Junhee Park / Jie Li / John P Mayer / Kerri A Ball / Jiayi Wu / Catherine Hall / Domenico Accili / Michael H B Stowell / Xiao-Chen Bai / Eunhee Choi / ![]() Abstract: Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity ...Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin's action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 241.1 KB | Display | ![]() |
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PDB format | ![]() | 164.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.1 MB | Display | ![]() |
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Full document | ![]() | 1.1 MB | Display | |
Data in XML | ![]() | 34.4 KB | Display | |
Data in CIF | ![]() | 48.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 27705MC ![]() 8dtlC 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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1 |
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Components
#1: Protein | Mass: 153232.578 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P15208, receptor protein-tyrosine kinase #2: Protein/peptide | | Mass: 2286.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) Has protein modification | Y | |
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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: Insulin receptor bound with S597 component 2 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES |
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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 |
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
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 2789169 | |||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | |||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 135709 / Symmetry type: POINT | |||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT |