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- EMDB-34018: human insulin receptor bound with A43 DNA aptamer and insulin -

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Basic information

Entry
Database: EMDB / ID: EMD-34018
Titlehuman insulin receptor bound with A43 DNA aptamer and insulin
Map data
Sample
  • Complex: receptor-ligand complex
    • Complex: Insulin, Insulin receptor
      • Protein or peptide: Insulin A chain
      • Protein or peptide: Insulin, isoform 2
      • Protein or peptide: Isoform Short of Insulin receptor
    • Complex: DNA 28mer
      • DNA: IR-A43 aptamer
Keywordsreceptor-ligand complex / 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 / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / 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 / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / dendritic spine maintenance / insulin binding / negative regulation of glycogen catabolic process / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / PTB domain binding / IRS activation / cargo receptor activity / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / positive regulation of peptide hormone secretion / negative regulation of acute inflammatory response / neuronal cell body membrane / positive regulation of respiratory burst / Regulation of gene expression in beta cells / relaxation of vascular associated smooth muscle / alpha-beta T cell activation / amyloid-beta clearance / acute-phase response / heart morphogenesis / positive regulation of receptor internalization / Synthesis, secretion, and deacylation of Ghrelin / insulin receptor substrate binding / negative regulation of gluconeogenesis / fatty acid homeostasis / negative regulation of protein secretion / positive regulation of brown fat cell differentiation / positive regulation of dendritic spine maintenance / positive regulation of insulin receptor signaling pathway / positive regulation of glycogen biosynthetic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / protein kinase activator activity / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of respiratory burst involved in inflammatory response / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / nitric oxide-cGMP-mediated signaling / regulation of protein localization to plasma membrane / phosphatidylinositol 3-kinase binding / Insulin receptor recycling / transport across blood-brain barrier / COPI-mediated anterograde transport / transport vesicle / positive regulation of nitric-oxide synthase activity / negative regulation of reactive oxygen species biosynthetic process / NPAS4 regulates expression of target genes / insulin-like growth factor receptor binding / positive regulation of D-glucose import across plasma membrane / positive regulation of mitotic nuclear division / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis / male gonad development / hormone activity / positive regulation of glycolytic process / regulation of embryonic development / Insulin receptor signalling cascade / learning / endosome lumen / dendrite membrane / positive regulation of protein secretion / wound healing / insulin receptor binding / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / positive regulation of neuron projection development / positive regulation of cell differentiation / negative regulation of protein catabolic process / Regulation of insulin secretion / memory / receptor protein-tyrosine kinase / vasodilation / positive regulation of protein localization to nucleus / regulation of synaptic plasticity / caveola / Golgi lumen / cognition / insulin receptor signaling pathway / positive regulation of nitric oxide biosynthetic process / cellular response to insulin stimulus / glucose homeostasis / late endosome / cell-cell signaling / protein autophosphorylation / positive regulation of cell growth / amyloid-beta binding / regulation of protein localization / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protease binding
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. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. ...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. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily / 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 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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
Insulin, isoform 2 / Insulin / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 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-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34018.png

Downloads & links

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Map

FileDownload / File: emd_34018.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 400 pix.
= 428. Å		1.07 Å/pix.
x 400 pix.
= 428. Å		1.07 Å/pix.
x 400 pix.
= 428. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-3.1139903 - 4.916215
Average (Standard dev.)-0.0010921069 (±0.07546248)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 428.00003 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_34018_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_34018_half_map_2.map
Projections & Slices
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Sample components

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Entire : receptor-ligand complex

EntireName: receptor-ligand complex
Components
  • Complex: receptor-ligand complex
    • Complex: Insulin, Insulin receptor
      • Protein or peptide: Insulin A chain
      • Protein or peptide: Insulin, isoform 2
      • Protein or peptide: Isoform Short of Insulin receptor
    • Complex: DNA 28mer
      • DNA: IR-A43 aptamer

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Supramolecule #1: receptor-ligand complex

SupramoleculeName: receptor-ligand complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Insulin, Insulin receptor

SupramoleculeName: Insulin, Insulin receptor / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3

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Supramolecule #3: DNA 28mer

SupramoleculeName: DNA 28mer / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4

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Macromolecule #1: Insulin A chain

MacromoleculeName: Insulin A chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.383698 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GIVEQCCTSI CSLYQLENYC N

UniProtKB: Insulin

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Macromolecule #2: Insulin, isoform 2

MacromoleculeName: Insulin, isoform 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.86025 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
NQHLCGSHLV EALYLVCGER GFFYT

UniProtKB: Insulin, isoform 2

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Macromolecule #3: Isoform Short of Insulin receptor

MacromoleculeName: Isoform Short of Insulin receptor / type: protein_or_peptide / ID: 3 / 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 #4: IR-A43 aptamer

MacromoleculeName: IR-A43 aptamer / type: dna / ID: 4 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 9.596608 KDa
SequenceString:
(DT)(DG)(85Y)(DA)(85Y)(DC)(DC)(DG)(DC)(DA) (DG)(85Y)(DA)(85Y)(DC)(DG)(DG)(DC)(DA) (85Y)(85Y)(DC)(DA)(DG)(DC)(DG)(DA)(DC)

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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: OTHER / 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

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 156334
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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