+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-10273 | |||||||||||||||
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Title | human insulin receptor ectodomain bound by 4 insulin | |||||||||||||||
Map data | "manually filtered map" in paper, b-factor=-140 | |||||||||||||||
Sample |
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Function / homology | Function and homology information regulation of female gonad development / positive regulation of meiotic cell cycle / positive regulation of developmental growth / insulin-like growth factor II binding / 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 / positive regulation of developmental growth / insulin-like growth factor II binding / 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 / negative regulation of NAD(P)H oxidase activity / neuronal cell body membrane / adrenal gland development / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / negative regulation of fatty acid metabolic process / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / amyloid-beta clearance / positive regulation of peptide hormone secretion / activation of protein kinase activity / Regulation of gene expression in beta cells / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / transport across blood-brain barrier / positive regulation of dendritic spine maintenance / alpha-beta T cell activation / negative regulation of acute inflammatory response / negative regulation of respiratory burst involved in inflammatory response / insulin receptor substrate binding / negative regulation of protein secretion / fatty acid homeostasis / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / positive regulation of glycogen biosynthetic process / positive regulation of lipid biosynthetic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / positive regulation of nitric oxide mediated signal transduction / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / phosphatidylinositol 3-kinase binding / negative regulation of lipid catabolic process / heart morphogenesis / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / dendrite membrane / Insulin receptor recycling / insulin-like growth factor receptor binding / receptor-mediated endocytosis / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / learning / Regulation of insulin secretion / positive regulation of nitric-oxide synthase activity / positive regulation of long-term synaptic potentiation / caveola / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of protein secretion / regulation of transmembrane transporter activity / positive regulation of cell differentiation / positive regulation of glucose import / negative regulation of proteolysis / regulation of synaptic plasticity / positive regulation of MAP kinase activity / wound healing / insulin receptor binding / negative regulation of protein catabolic process / positive regulation of neuron projection development / hormone activity / receptor internalization / receptor protein-tyrosine kinase / memory / cellular response to growth factor stimulus / cognition / Golgi lumen / vasodilation / positive regulation of protein localization to nucleus Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.3 Å | |||||||||||||||
Authors | Gutmann T / Schaefer IB / Poojari CS / Vattulainen I / Strauss M / Coskun U | |||||||||||||||
Funding support | Germany, Finland, 4 items
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Citation | Journal: J Cell Biol / Year: 2020 Title: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain. Authors: Theresia Gutmann / Ingmar B Schäfer / Chetan Poojari / Beate Brankatschk / Ilpo Vattulainen / Mike Strauss / Ünal Coskun / Abstract: Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current ...Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design. #1: Journal: bioRxiv / Year: 2019 Title: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain Authors: Gutmann T / Schafer IB / Poojari C / Brankatschk B / Vattulainen I / Strauss M / Coskun U | |||||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_10273.map.gz | 59.6 MB | EMDB map data format | |
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Header (meta data) | emd-10273-v30.xml emd-10273.xml | 24.9 KB 24.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_10273_fsc.xml | 10.3 KB | Display | FSC data file |
Images | emd_10273.png | 181.8 KB | ||
Masks | emd_10273_msk_1.map | 91.1 MB | Mask map | |
Others | emd_10273_additional.map.gz emd_10273_half_map_1.map.gz emd_10273_half_map_2.map.gz | 6.3 MB 71.2 MB 71.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-10273 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-10273 | HTTPS FTP |
-Related structure data
Related structure data | 6sofMC 7qidC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_10273.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | "manually filtered map" in paper, b-factor=-140 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_10273_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: "automatically filtered map" in paper, b-factor=-172
File | emd_10273_additional.map | ||||||||||||
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Annotation | "automatically filtered map" in paper, b-factor=-172 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half-map 1 post Bayesian polishing
File | emd_10273_half_map_1.map | ||||||||||||
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Annotation | half-map 1 post Bayesian polishing | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half-map 2 post Bayesian polishing
File | emd_10273_half_map_2.map | ||||||||||||
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Annotation | half-map 2 post Bayesian polishing | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : human insulin receptor ectodomain bound to four insulin
Entire | Name: human insulin receptor ectodomain bound to four insulin |
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Components |
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-Supramolecule #1: human insulin receptor ectodomain bound to four insulin
Supramolecule | Name: human insulin receptor ectodomain bound to four insulin type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Molecular weight | Experimental: 375 KDa |
-Supramolecule #2: human insulin receptor ectodomain bound to four insulin
Supramolecule | Name: human insulin receptor ectodomain bound to four insulin type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Supramolecule #3: human insulin receptor ectodomain bound to four insulin
Supramolecule | Name: human insulin receptor ectodomain bound to four insulin type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Saccharomyces cerevisiae (brewer's yeast) |
-Macromolecule #1: Insulin receptor
Macromolecule | Name: Insulin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 82.551742 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDIC P GTAKGKTN ...String: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDIC P GTAKGKTN CPATVINGQF VERCWTHSHC QKVCPTICKS HGCTAEGLCC HSECLGNCSQ PDDPTKCVAC RNFYLDGRCV ET CPPPYYH FQDWRCVNFS FCQDLHHKCK NSRRQGCHQY VIHNNKCIPE CPSGYTMNSS NLLCTPCLGP CPKVCHLLEG EKT IDSVTS AQELRGCTVI NGSLIINIRG GNNLAAELEA NLGLIEEISG YLKIRRSYAL VSLSFFRKLR LIRGETLEIG NYSF YALDN QNLRQLWDWS KHNLTITQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDQ ASCENELLKF SYIRT SFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN VTEFDGQDAC GSNSWTVVDI DPPLRSNDPK SQNHPGWLMR GLKPWT QYA IFVKTLVTFS DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSE LF ELDYCLKGLK LPSRTWSPPF ESEDSQKHNQ SEYEDSAGEC CSCPKTDSQI LKELEESSFR KTFEDYLHNV VFVPRPS |
-Macromolecule #2: Insulin receptor
Macromolecule | Name: Insulin receptor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 18.5139 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: HRPFEKVVNK ESLVISGLRH FTGYRIELQA CNQDTPEERC SVAAYVSART MPEAKADDIV GPVTHEIFEN NVVHLMWQEP KEPNGLIVL YEVSYRRYGD EELHLCVSRK HFALERGCRL RGLSPGNYSV RIRATSLAGN GSWTEPTYFY VTDYLDVPSN I AK |
-Macromolecule #3: Insulin
Macromolecule | Name: Insulin / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 2.383698 KDa |
Recombinant expression | Organism: Saccharomyces cerevisiae (brewer's yeast) |
Sequence | String: GIVEQCCTSI CSLYQLENYC N |
-Macromolecule #4: Insulin
Macromolecule | Name: Insulin / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 3.433953 KDa |
Recombinant expression | Organism: Saccharomyces cerevisiae (brewer's yeast) |
Sequence | String: FVNQHLCGSH LVEALYLVCG ERGFFYTPKT |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 51 / Average exposure time: 10.2 sec. / Average electron dose: 55.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |