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- PDB-7sl3: Full-length insulin receptor bound with site 2 binding deficient ... -

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Basic information

Entry
Database: PDB / ID: 7sl3
TitleFull-length insulin receptor bound with site 2 binding deficient mutant insulin (A-L13R) -- symmetric conformation
Components
  • Insulin A chain
  • Insulin B chain
  • Insulin receptor
KeywordsSIGNALING PROTEIN/HORMONE / insulin receptor / site 1 binding deficient mutant insulin / SIGNALING PROTEIN / SIGNALING PROTEIN-HORMONE complex
Function / homology
Function and homology information


Signaling by Insulin receptor / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth ...Signaling by Insulin receptor / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 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 / nuclear lumen / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / exocrine pancreas development / insulin binding / adrenal gland development / negative regulation of glycogen catabolic process / PTB domain binding / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / alpha-beta T cell activation / positive regulation of receptor internalization / insulin receptor substrate binding / regulation of embryonic development / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of dendritic spine maintenance / epidermis development / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / protein kinase activator activity / positive regulation of insulin receptor signaling pathway / negative regulation of respiratory burst involved in inflammatory response / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / heart morphogenesis / regulation of protein localization to plasma membrane / 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 / positive regulation of brown fat cell differentiation / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of glycolytic process / animal organ morphogenesis / positive regulation of cytokine production / endosome lumen / acute-phase response / positive regulation of long-term synaptic potentiation / positive regulation of D-glucose import across plasma membrane / positive regulation of protein secretion / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / wound healing / positive regulation of neuron projection development / hormone activity / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / regulation of synaptic plasticity / caveola / receptor internalization / positive regulation of protein localization to nucleus / Golgi lumen / cellular response to growth factor stimulus / vasodilation / male gonad development / cognition / recycling endosome membrane / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / insulin receptor signaling pathway / late endosome / nuclear envelope / cell-cell signaling / glucose homeostasis / regulation of protein localization
Similarity search - Function
24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / 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. / Alpha-Beta Horseshoe / Insulin / Insulin family ...24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / 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. / Alpha-Beta Horseshoe / 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 / 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 / Alpha Beta
Similarity search - Domain/homology
Insulin / Insulin receptor
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsBai, X.C. / Choi, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM136976 United States
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Synergistic activation of the insulin receptor via two distinct sites.
Authors: Jie Li / Junhee Park / John P Mayer / Kristofor J Webb / Emiko Uchikawa / Jiayi Wu / Shun Liu / Xuewu Zhang / Michael H B Stowell / Eunhee Choi / Xiao-Chen Bai /
Abstract: Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional ...Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation.
History
DepositionOct 22, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 13, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 27, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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
A: Insulin receptor
B: Insulin receptor
C: Insulin B chain
D: Insulin B chain
E: Insulin A chain
F: Insulin A chain


Theoretical massNumber of molelcules
Total (without water)323,3046
Polymers323,3046
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Insulin receptor / IR


Mass: 155790.516 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Insr / Production host: Homo sapiens (human)
References: UniProt: P15208, receptor protein-tyrosine kinase
#2: Protein/peptide Insulin B chain


Mass: 3433.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Homo sapiens (human) / References: UniProt: P01308
#3: Protein/peptide Insulin A chain


Mass: 2427.734 Da / Num. of mol.: 2 / Mutation: L13R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Homo sapiens (human) / References: UniProt: P01308
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: Full-length insulin receptor bound with site 2 binding deficient mutant insulin (A-L13R) -- symmetric conformation
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Buffer solutionpH: 8
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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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: 2600 nm / Nominal defocus min: 1600 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELIONparticle selection
2SerialEM3image acquisition
4GctfCTF correction
7Coot0.9model fitting
9PHENIX1.19model refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1118695
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 104877 / Symmetry type: POINT

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