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- PDB-9jhs: Human insulin receptor bound with A62-dimer, arrowhead conformation -

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Basic information

Entry
Database: PDB / ID: 9jhs
TitleHuman insulin receptor bound with A62-dimer, arrowhead conformation
Components
  • DNA/RNA (5'-D(P*CP*(AF2)P*(DUZ)P*(DUZ)P*AP*(CFZ)P*GP*(CFZ)P*A)-R(P*(85Y)P*(OMG))-D(P*(AF2))-R(P*(OMG))-D(P*(DUZ)P*C)-R(P*(85Y))-D(P*AP*GP*(AF2))-R(P*(85Y)P*(OMC))-D(P*(CFZ)P*GP*(DUZ))-3')
  • Insulin receptor
KeywordsMEMBRANE PROTEIN / diabetes / signaling / agonist / aptamer / 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 / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / insulin receptor activity / exocrine pancreas development ...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 / positive regulation of protein-containing complex disassembly / insulin receptor activity / exocrine pancreas development / dendritic spine maintenance / cargo receptor activity / insulin binding / adrenal gland development / PTB domain binding / neuronal cell body membrane / Signaling by Insulin receptor / IRS activation / positive regulation of respiratory burst / amyloid-beta clearance / regulation of embryonic development / insulin receptor substrate binding / positive regulation of receptor internalization / epidermis development / protein kinase activator activity / positive regulation of glycogen biosynthetic process / Signal attenuation / heart morphogenesis / transport across blood-brain barrier / phosphatidylinositol 3-kinase binding / Insulin receptor recycling / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / Insulin receptor signalling cascade / positive regulation of glycolytic process / positive regulation of D-glucose import across plasma membrane / learning / receptor protein-tyrosine kinase / caveola / receptor internalization / cellular response to growth factor stimulus / memory / male gonad development / cellular response to insulin stimulus / positive regulation of nitric oxide biosynthetic process / insulin receptor signaling pathway / late endosome / glucose homeostasis / amyloid-beta binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / lysosome / positive regulation of canonical NF-kappaB signal transduction / 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 / G protein-coupled receptor signaling pathway / protein domain specific binding / axon / external side of plasma membrane / positive regulation of cell population proliferation / regulation of DNA-templated transcription / symbiont entry into host cell / positive regulation of DNA-templated transcription / GTP binding / protein-containing complex binding / 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 / Fibronectin type III domain / 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 / 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
DNA / DNA (> 10) / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.02 Å
AuthorsKim, J. / Na, H. / Yunn, N. / Ryu, S. / Cho, Y.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea) Korea, Republic Of
CitationJournal: Exp Mol Med / Year: 2025
Title: Structural mechanism of insulin receptor activation by a dimeric aptamer agonist.
Authors: Junhong Kim / Hyeonjin Na / Si-Young Choi / Eun Ju Oh / Hyunsook Lee / Sung Ho Ryu / Na-Oh Yunn / Yunje Cho /
Abstract: Insulin binding to the insulin receptor (IR) triggers signaling pathways that regulate glucose uptake and cell growth. In previous work, we identified a DNA aptamer, A62, which partially activates ...Insulin binding to the insulin receptor (IR) triggers signaling pathways that regulate glucose uptake and cell growth. In previous work, we identified a DNA aptamer, A62, which partially activates the IR. During engineering aptamers for improved in vivo stability, we discovered that crosslinking two A62 aptamers with linkers of varying lengths led to full phosphorylation of the IR, although activation remained selective to the AKT pathway. Here, to elucidate the mechanism behind this aptamer-induced full activation of the IR, we determined the structure of the IR in complex with a dimeric form of A62 (A62D) linked by an eight-nucleotide connector. We identified three distinct conformations of the IR: arrowhead-shaped, pseudo-arrowhead-shaped and pseudo-gamma-shaped. The pseudo-gamma-shaped conformation closely resembles the structure of a fully active IR bound by a single insulin molecule. In these configurations, only one A62 monomer (A62M) within the A62D dimer binds to the IR dimer. This binding brings the IR monomers into close proximity, promoting intermolecular trans-phosphorylation. Our findings provide valuable structural insights for the development of novel therapeutic strategies targeting the IR.
History
DepositionSep 10, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release
Revision 1.1Aug 20, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Insulin receptor
F: Insulin receptor
G: DNA/RNA (5'-D(P*CP*(AF2)P*(DUZ)P*(DUZ)P*AP*(CFZ)P*GP*(CFZ)P*A)-R(P*(85Y)P*(OMG))-D(P*(AF2))-R(P*(OMG))-D(P*(DUZ)P*C)-R(P*(85Y))-D(P*AP*GP*(AF2))-R(P*(85Y)P*(OMC))-D(P*(CFZ)P*GP*(DUZ))-3')
H: DNA/RNA (5'-D(P*CP*(AF2)P*(DUZ)P*(DUZ)P*AP*(CFZ)P*GP*(CFZ)P*A)-R(P*(85Y)P*(OMG))-D(P*(AF2))-R(P*(OMG))-D(P*(DUZ)P*C)-R(P*(85Y))-D(P*AP*GP*(AF2))-R(P*(85Y)P*(OMC))-D(P*(CFZ)P*GP*(DUZ))-3')


Theoretical massNumber of molelcules
Total (without water)226,6794
Polymers226,6794
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Insulin receptor / IR


Mass: 104812.828 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Homo sapiens (human)
References: UniProt: P06213, receptor protein-tyrosine kinase
#2: DNA chain DNA/RNA (5'-D(P*CP*(AF2)P*(DUZ)P*(DUZ)P*AP*(CFZ)P*GP*(CFZ)P*A)-R(P*(85Y)P*(OMG))-D(P*(AF2))-R(P*(OMG))-D(P*(DUZ)P*C)-R(P*(85Y))-D(P*AP*GP*(AF2))-R(P*(85Y)P*(OMC))-D(P*(CFZ)P*GP*(DUZ))-3')


Mass: 8526.799 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human insulin receptor and aptamer complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2 nm / Nominal defocus min: 1 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 5.02 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 48970 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00314449
ELECTRON MICROSCOPYf_angle_d0.8419812
ELECTRON MICROSCOPYf_dihedral_angle_d16.9752082
ELECTRON MICROSCOPYf_chiral_restr0.0472109
ELECTRON MICROSCOPYf_plane_restr0.0052395

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