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Yorodumi- EMDB-26363: Head region of insulin receptor ectodomain (A-isoform) bound to t... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-26363 | |||||||||
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Title | Head region of insulin receptor ectodomain (A-isoform) bound to the non-insulin agonist IM459 | |||||||||
Map data | Focused reconstruction of IM459 bound to IR-A(ecto) | |||||||||
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 / adrenal gland development / Signaling by Insulin receptor / activation of protein kinase activity / IRS activation / neuronal cell body membrane / positive regulation of respiratory burst / positive regulation of receptor internalization / amyloid-beta clearance / transport across blood-brain barrier / regulation of embryonic development / insulin receptor substrate binding / positive regulation of glycogen biosynthetic process / epidermis development / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / insulin-like growth factor receptor binding / Insulin receptor recycling / dendrite membrane / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / learning / positive regulation of D-glucose import / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / caveola / receptor internalization / cellular response to growth factor stimulus / memory / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / male gonad development / positive regulation of nitric oxide biosynthetic process / late endosome / insulin receptor signaling pathway / glucose homeostasis / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein autophosphorylation / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / lysosome / 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 / protein phosphorylation / external side of plasma membrane / axon / positive regulation of cell population proliferation / GTP binding / protein-containing complex binding / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / extracellular exosome / ATP binding / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 5.03 Å | |||||||||
Authors | Kirk NS / Lawrence MC | |||||||||
Funding support | United States, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_26363.map.gz | 230 MB | EMDB map data format | |
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Header (meta data) | emd-26363-v30.xml emd-26363.xml | 15.3 KB 15.3 KB | Display Display | EMDB header |
Images | emd_26363.png | 36.4 KB | ||
Others | emd_26363_half_map_1.map.gz emd_26363_half_map_2.map.gz | 226.7 MB 226.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-26363 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-26363 | HTTPS FTP |
-Validation report
Summary document | emd_26363_validation.pdf.gz | 966.6 KB | Display | EMDB validaton report |
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Full document | emd_26363_full_validation.pdf.gz | 966.2 KB | Display | |
Data in XML | emd_26363_validation.xml.gz | 16 KB | Display | |
Data in CIF | emd_26363_validation.cif.gz | 19 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26363 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26363 | HTTPS FTP |
-Related structure data
Related structure data | 7u6dMC 7u6eC 8di2C C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_26363.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | Focused reconstruction of IM459 bound to IR-A(ecto) | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Half-map B of focused reconstruction of IM459 bound to IR-A(ecto)
File | emd_26363_half_map_1.map | ||||||||||||
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Annotation | Half-map B of focused reconstruction of IM459 bound to IR-A(ecto) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half-map A of focused reconstruction of IM459 bound to IR-A(ecto)
File | emd_26363_half_map_2.map | ||||||||||||
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Annotation | Half-map A of focused reconstruction of IM459 bound to IR-A(ecto) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Complex of non-insulin insulin receptor agonist IM459 bound to th...
Entire | Name: Complex of non-insulin insulin receptor agonist IM459 bound to the insulin receptor ectodomain (A-isoform) construct IR-A(ecto) |
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Components |
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-Supramolecule #1: Complex of non-insulin insulin receptor agonist IM459 bound to th...
Supramolecule | Name: Complex of non-insulin insulin receptor agonist IM459 bound to the insulin receptor ectodomain (A-isoform) construct IR-A(ecto) type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: IM459
Macromolecule | Name: IM459 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 4.000595 KDa |
Sequence | String: SLEQEW(AIB)KIE CEVYGKCPPK KA(0A1)YDWFERQ LK |
-Macromolecule #2: Isoform Short of Insulin receptor
Macromolecule | Name: Isoform Short of 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: 104.607664 KDa |
Recombinant expression | Organism: Cricetulus griseus (Chinese hamster) |
Sequence | String: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNHIVLNK DDNEECGDIC P GTAKGKTN ...String: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNHIVLNK 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 VFVPRPSR K RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAY VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRIRAT SLAGNGSWTE PTYFYVTDYL DVPSNIA |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 69.5 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.0 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 5.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 184000 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |