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- EMDB-34021: human insulin receptor bound with A62 DNA aptamer -

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Basic information

Entry
Database: EMDB / ID: EMD-34021
Titlehuman insulin receptor bound with A62 DNA aptamer
Map data
Sample
  • Complex: receptor_ligand complex C
    • Complex: Insulin receptor
      • Protein or peptide: Isoform Short of Insulin receptor
    • Complex: DNA
      • DNA: IR-A62 aptamer
Keywordsreceptor-ligand complex_C / STRUCTURAL PROTEIN
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 / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / dendritic spine maintenance ...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 / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / dendritic spine maintenance / cargo receptor activity / insulin binding / neuronal cell body membrane / adrenal gland development / PTB domain binding / Signaling by Insulin receptor / IRS activation / positive regulation of respiratory burst / amyloid-beta clearance / 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 / Signal attenuation / phosphatidylinositol 3-kinase binding / transport across blood-brain barrier / heart morphogenesis / activation of protein kinase B activity / Insulin receptor recycling / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / positive regulation of MAP kinase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / positive regulation of glycolytic process / learning / positive regulation of D-glucose import / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / caveola / receptor internalization / memory / 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 / positive regulation of protein phosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / protein tyrosine kinase activity / positive regulation of canonical NF-kappaB signal transduction / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / endosome membrane / positive regulation of cell migration / protein phosphorylation / G protein-coupled receptor signaling pathway / protein domain specific binding / symbiont entry into host cell / axon / external side of plasma membrane / positive regulation of cell population proliferation / regulation of DNA-templated transcription / protein-containing complex binding / GTP binding / positive regulation of DNA-templated transcription / extracellular exosome / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Fibronectin type III domain / : / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.18 Å
AuthorsKim J / Yunn N / Ryu S / Cho Y
Funding support Korea, Republic Of, 1 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)2017M3A9F6029736 Korea, Republic Of
CitationJournal: Nat Commun / Year: 2022
Title: Functional selectivity of insulin receptor revealed by aptamer-trapped receptor structures.
Authors: Junhong Kim / Na-Oh Yunn / Mangeun Park / Jihan Kim / Seongeun Park / Yoojoong Kim / Jeongeun Noh / Sung Ho Ryu / Yunje Cho /
Abstract: Activation of insulin receptor (IR) initiates a cascade of conformational changes and autophosphorylation events. Herein, we determined three structures of IR trapped by aptamers using cryo-electron ...Activation of insulin receptor (IR) initiates a cascade of conformational changes and autophosphorylation events. Herein, we determined three structures of IR trapped by aptamers using cryo-electron microscopy. The A62 agonist aptamer selectively activates metabolic signaling. In the absence of insulin, the two A62 aptamer agonists of IR adopt an insulin-accessible arrowhead conformation by mimicking site-1/site-2' insulin coordination. Insulin binding at one site triggers conformational changes in one protomer, but this movement is blocked in the other protomer by A62 at the opposite site. A62 binding captures two unique conformations of IR with a similar stalk arrangement, which underlie Tyr1150 mono-phosphorylation (m-pY1150) and selective activation for metabolic signaling. The A43 aptamer, a positive allosteric modulator, binds at the opposite side of the insulin-binding module, and stabilizes the single insulin-bound IR structure that brings two FnIII-3 regions into closer proximity for full activation. Our results suggest that spatial proximity of the two FnIII-3 ends is important for m-pY1150, but multi-phosphorylation of IR requires additional conformational rearrangement of intracellular domains mediated by coordination between extracellular and transmembrane domains.
History
DepositionAug 5, 2022-
Header (metadata) releaseNov 9, 2022-
Map releaseNov 9, 2022-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34021.png

Downloads & links

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Map

FileDownload / File: emd_34021.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.2581686 - 2.155848
Average (Standard dev.)0.0034861364 (±0.04535786)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 321.00003 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_34021_half_map_1.map
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Half map: #2

Fileemd_34021_half_map_2.map
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Sample components

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Entire : receptor_ligand complex C

EntireName: receptor_ligand complex C
Components
  • Complex: receptor_ligand complex C
    • Complex: Insulin receptor
      • Protein or peptide: Isoform Short of Insulin receptor
    • Complex: DNA
      • DNA: IR-A62 aptamer

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Supramolecule #1: receptor_ligand complex C

SupramoleculeName: receptor_ligand complex C / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Insulin receptor

SupramoleculeName: Insulin receptor / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: DNA

SupramoleculeName: DNA / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: Isoform Short of Insulin receptor

MacromoleculeName: Isoform Short of Insulin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 103.623578 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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 KHNLTTTQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDK 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 PTYFYVTD

UniProtKB: Insulin receptor

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Macromolecule #2: IR-A62 aptamer

MacromoleculeName: IR-A62 aptamer / type: dna / ID: 2 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 8.526799 KDa
SequenceString:
(DC)(AF2)(DUZ)(DUZ)(DA)(CFZ)(DG)(CFZ)(DA)(85Y) (OMG)(AF2)(OMG)(DUZ)(DC)(85Y)(DA) (DG)(AF2) (85Y)(OMC)(CFZ)(DG)(DUZ)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.18 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 181797
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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