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Yorodumi- PDB-7u6d: Head region of insulin receptor ectodomain (A-isoform) bound to t... -
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-Basic information
Entry | Database: PDB / ID: 7u6d | ||||||
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Title | Head region of insulin receptor ectodomain (A-isoform) bound to the non-insulin agonist IM459 | ||||||
Components |
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Keywords | SIGNALING PROTEIN/AGONIST / insulin receptor / insulin-mimic peptide / insulin receptor agonist / SIGNALING PROTEIN-AGONIST complex | ||||||
Function / homology | Function and homology information regulation of female gonad development / positive regulation of meiotic cell cycle / 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 protein-containing complex disassembly ...regulation of female gonad development / positive regulation of meiotic cell cycle / 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 protein-containing complex disassembly / cargo receptor activity / dendritic spine maintenance / insulin binding / PTB domain binding / adrenal gland development / Signaling by Insulin receptor / IRS activation / activation of protein kinase activity / neuronal cell body membrane / amyloid-beta clearance / positive regulation of respiratory burst / positive regulation of receptor internalization / regulation of embryonic development / insulin receptor substrate binding / transport across blood-brain barrier / positive regulation of glycogen biosynthetic process / epidermis development / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / 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 / receptor-mediated endocytosis / positive regulation of MAP kinase activity / learning / caveola / positive regulation of glucose import / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / receptor internalization / memory / cellular response to growth factor stimulus / male gonad development / positive regulation of nitric oxide biosynthetic process / glucose homeostasis / late endosome / insulin receptor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / amyloid-beta binding / protein tyrosine kinase activity / protein autophosphorylation / receptor complex / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / endosome membrane / lysosome / positive regulation of cell migration / positive regulation of protein phosphorylation / symbiont entry into host cell / protein domain specific binding / G protein-coupled receptor signaling pathway / protein phosphorylation / external side of plasma membrane / axon / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / regulation of DNA-templated transcription / protein-containing complex binding / GTP binding / extracellular exosome / ATP binding / identical protein binding / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.03 Å | ||||||
Authors | Kirk, N.S. / Lawrence, M.C. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Commun / Year: 2022 Title: Activation of the human insulin receptor by non-insulin-related peptides. Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David ...Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David G Barrett / Michael C Lawrence / Abstract: The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in ...The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from-but related to-those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7u6d.cif.gz | 197.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7u6d.ent.gz | 146.1 KB | Display | PDB format |
PDBx/mmJSON format | 7u6d.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7u6d_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 7u6d_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 7u6d_validation.xml.gz | 39.7 KB | Display | |
Data in CIF | 7u6d_validation.cif.gz | 55.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/u6/7u6d ftp://data.pdbj.org/pub/pdb/validation_reports/u6/7u6d | HTTPS FTP |
-Related structure data
Related structure data | 26363MC 7u6eC 8di2C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein/peptide | Mass: 4000.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) | ||
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#2: Protein | Mass: 104607.664 Da / Num. of mol.: 2 / Fragment: ectodomain (UNP residues 28-943) Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Cricetulus griseus (Chinese hamster) References: UniProt: P06213, receptor protein-tyrosine kinase Has ligand of interest | N | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Complex of non-insulin insulin receptor agonist IM459 bound to the insulin receptor ectodomain (A-isoform) construct IR-A(ecto) Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Cricetulus griseus (Chinese hamster) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 4000 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 69.5 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19.2_4158: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 5.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 184000 / Symmetry type: POINT | ||||||||||||||||||||||||
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