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- PDB-7yq4: human insulin receptor bound with A62 DNA aptamer and insulin - l... -

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Basic information

Entry
Database: PDB / ID: 7yq4
Titlehuman insulin receptor bound with A62 DNA aptamer and insulin - locally refined
Components
  • IR-A62 aptamer
  • Insulin A chain
  • Insulin, isoform 2
  • Isoform Short of Insulin receptor
KeywordsSTRUCTURAL PROTEIN / receptor-ligand complex_B_local
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 / exocrine pancreas development / insulin-like growth factor I binding / 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 / exocrine pancreas development / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / dendritic spine maintenance / cargo receptor activity / insulin binding / negative regulation of NAD(P)H oxidase activity / PTB domain binding / adrenal gland development / neuronal cell body membrane / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / Regulation of gene expression in beta cells / positive regulation of respiratory burst / amyloid-beta clearance / negative regulation of acute inflammatory response / regulation of embryonic development / alpha-beta T cell activation / positive regulation of receptor internalization / protein kinase activator activity / insulin receptor substrate binding / regulation of amino acid metabolic process / positive regulation of dendritic spine maintenance / negative regulation of respiratory burst involved in inflammatory response / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / negative regulation of protein secretion / negative regulation of gluconeogenesis / fatty acid homeostasis / positive regulation of glycogen biosynthetic process / phosphatidylinositol 3-kinase binding / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / transport across blood-brain barrier / negative regulation of lipid catabolic process / COPI-mediated anterograde transport / regulation of protein localization to plasma membrane / positive regulation of lipid biosynthetic process / positive regulation of insulin receptor signaling pathway / heart morphogenesis / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of protein autophosphorylation / nitric oxide-cGMP-mediated signaling / activation of protein kinase B activity / transport vesicle / negative regulation of reactive oxygen species biosynthetic process / dendrite membrane / Insulin receptor recycling / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of MAP kinase activity / positive regulation of nitric-oxide synthase activity / positive regulation of glycolytic process / learning / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / endosome lumen / acute-phase response / negative regulation of proteolysis / positive regulation of D-glucose import / positive regulation of protein secretion / positive regulation of cell differentiation / Regulation of insulin secretion / insulin receptor binding / regulation of transmembrane transporter activity / wound healing / 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 / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity
Similarity search - Function
Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / 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 ...Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / 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 / Ribbon / 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 / Mainly Beta
Similarity search - Domain/homology
DNA / DNA (> 10) / Insulin, isoform 2 / Insulin / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.95 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
DepositionAug 5, 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 1.2Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: Isoform Short of Insulin receptor
B: Insulin, isoform 2
A: Insulin A chain
F: Isoform Short of Insulin receptor
G: IR-A62 aptamer


Theoretical massNumber of molelcules
Total (without water)221,0185
Polymers221,0185
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10710 Å2
ΔGint-31 kcal/mol
Surface area68310 Å2

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Components

#1: Protein Isoform Short of Insulin receptor


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
#2: Protein/peptide Insulin, isoform 2 / INS-IGF2 readthrough transcript protein


Mass: 2860.250 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS-IGF2 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: F8WCM5
#3: Protein/peptide Insulin A chain / Small chain


Mass: 2383.698 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P01308
#4: DNA chain IR-A62 aptamer


Mass: 8526.799 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
Has ligand of interestY
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-complex_B_localCOMPLEXall0MULTIPLE SOURCES
2Insulin, Insulin receptorCOMPLEX#1-#31RECOMBINANT
3DNACOMPLEX#41SYNTHETIC
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: 2250 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 163150 / Symmetry type: POINT

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