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- PDB-8guy: human insulin receptor bound with two insulin molecules -

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Basic information

Entry
Database: PDB / ID: 8guy
Titlehuman insulin receptor bound with two insulin molecules
Components
  • Insulin A chain
  • Insulin, isoform 2
  • Isoform Short of Insulin receptor
KeywordsSTRUCTURAL PROTEIN / receptor-ligand 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 / exocrine pancreas 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 / male sex determination / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / exocrine pancreas development / dendritic spine maintenance / cargo receptor activity / insulin binding / adrenal gland development / neuronal cell body membrane / negative regulation of glycogen catabolic process / PTB domain binding / positive regulation of nitric oxide mediated signal transduction / negative regulation of feeding behavior / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / amyloid-beta clearance / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / alpha-beta T cell activation / regulation of embryonic development / positive regulation of receptor internalization / insulin receptor substrate binding / protein kinase activator activity / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / epidermis development / negative regulation of protein secretion / activation of protein kinase B activity / negative regulation of gluconeogenesis / positive regulation of insulin receptor signaling pathway / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / insulin receptor activity / heart morphogenesis / positive regulation of lipid biosynthetic process / transport across blood-brain barrier / regulation of protein localization to plasma membrane / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / phosphatidylinositol 3-kinase binding / transport vesicle / nitric oxide-cGMP-mediated signaling / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / Insulin receptor recycling / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / dendrite membrane / endoplasmic reticulum-Golgi intermediate compartment membrane / neuron projection maintenance / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / positive regulation of glycolytic process / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / endosome lumen / acute-phase response / positive regulation of protein secretion / positive regulation of D-glucose import / learning / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / wound healing / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / hormone activity / positive regulation of neuron projection development / regulation of synaptic plasticity / caveola / cellular response to growth factor stimulus / receptor internalization / positive regulation of protein localization to nucleus / Golgi lumen / cognition / memory / cellular response to insulin stimulus / glucose metabolic process / male gonad development / positive regulation of nitric oxide biosynthetic process / vasodilation / late endosome / insulin receptor signaling pathway / glucose homeostasis
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 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
Insulin, isoform 2 / Insulin / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.18 Å
AuthorsKim, J. / Yunn, N. / Ryu, S. / Cho, Y.
Funding support Korea, Republic Of, 1items
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
DepositionSep 14, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: Isoform Short of Insulin receptor
A: Insulin A chain
B: Insulin, isoform 2
C: Insulin A chain
D: Insulin, isoform 2
F: Isoform Short of Insulin receptor


Theoretical massNumber of molelcules
Total (without water)217,7356
Polymers217,7356
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Isoform Short of Insulin receptor / IR


Mass: 103623.578 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: P06213, receptor protein-tyrosine kinase
#2: Protein/peptide Insulin A chain / Small chain


Mass: 2383.698 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308
#3: Protein/peptide Insulin, isoform 2 / INS-IGF2 readthrough transcript protein


Mass: 2860.250 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS-IGF2 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: F8WCM5
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

Component
IDNameTypeEntity IDParent-IDSource
1receptor-ligand complexCOMPLEXall0RECOMBINANT
2receptor_ligand_complexCOMPLEX#11RECOMBINANT
3ligandCOMPLEX#2-#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Saccharomyces cerevisiae (brewer's yeast)4932
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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 4.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 127787 / Symmetry type: POINT

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