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- PDB-6vwi: Head region of the closed conformation of the human type 1 insuli... -

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Entry
Database: PDB / ID: 6vwi
TitleHead region of the closed conformation of the human type 1 insulin-like growth factor receptor ectodomain in complex with human insulin-like growth factor II.
Components
  • Insulin-like growth factor II
  • Leucine-zippered human type 1 insulin-like growth factor receptor ectodomain
KeywordsSIGNALING PROTEIN / Type 1 insulin-like growth factor receptor / Insulin-like growth factor II / ectodomain receptor / tyrosine kinase
Function / homology
Function and homology information


embryonic placenta morphogenesis / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / protein kinase complex / insulin-like growth factor receptor activity / insulin-like growth factor binding / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R ...embryonic placenta morphogenesis / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / protein kinase complex / insulin-like growth factor receptor activity / insulin-like growth factor binding / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / transcytosis / FCERI mediated MAPK activation / protein localization to nuclear periphery / Activation of the AP-1 family of transcription factors / positive regulation of organ growth / response to amino acid starvation / negative regulation of ribosomal protein gene transcription by RNA polymerase II / positive regulation of cellular response to amino acid starvation / mediator complex binding / genomic imprinting / transmembrane receptor protein tyrosine kinase activator activity / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / insulin receptor activity / positive regulation of multicellular organism growth / Oxidative Stress Induced Senescence / exocrine pancreas development / alphav-beta3 integrin-IGF-1-IGF1R complex / dendritic spine maintenance / regulation of JNK cascade / positive regulation of vascular endothelial cell proliferation / peptidyl-tyrosine autophosphorylation / insulin binding / amyloid-beta clearance / TFIID-class transcription factor complex binding / positive regulation of activated T cell proliferation / amino acid biosynthetic process / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of cell division / insulin receptor substrate binding / positive regulation of RNA polymerase II transcription preinitiation complex assembly / positive regulation of insulin receptor signaling pathway / positive regulation of glycogen biosynthetic process / positive regulation of transcription initiation by RNA polymerase II / embryonic placenta development / SHC-related events triggered by IGF1R / cellular response to nutrient levels / phosphatidylinositol 3-kinase binding / negative regulation of MAPK cascade / insulin-like growth factor receptor binding / striated muscle cell differentiation / positive regulation of mitotic nuclear division / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / cellular response to amino acid starvation / animal organ morphogenesis / protein serine/threonine kinase activator activity / insulin receptor binding / growth factor activity / cellular response to glucose stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor protein-tyrosine kinase / hormone activity / RNA polymerase II transcription regulator complex / integrin binding / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / glucose metabolic process / cellular response to amyloid-beta / osteoblast differentiation / insulin receptor signaling pathway / Platelet degranulation / positive regulation of cold-induced thermogenesis / protein autophosphorylation / DNA-binding transcription activator activity, RNA polymerase II-specific / protein tyrosine kinase activity / transcription regulator complex / sequence-specific DNA binding / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / DNA-binding transcription factor activity, RNA polymerase II-specific / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / intracellular signal transduction / immune response / cilium / positive regulation of cell migration / RNA polymerase II cis-regulatory region sequence-specific DNA binding / receptor ligand activity / DNA-binding transcription factor activity / axon / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / chromatin binding / regulation of DNA-templated transcription / negative regulation of apoptotic process / nucleolus / negative regulation of transcription by RNA polymerase II
Similarity search - Function
Insulin-like growth factor II E-peptide, C-terminal / Insulin-like growth factor II / Insulin-like growth factor II E-peptide / Insulin-like, subunit E / Insulin-like / Insulin-like growth factor / 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / : / Basic region leucine zipper ...Insulin-like growth factor II E-peptide, C-terminal / Insulin-like growth factor II / Insulin-like growth factor II E-peptide / Insulin-like, subunit E / Insulin-like / Insulin-like growth factor / 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / : / Basic region leucine zipper / Tyrosine-protein kinase, insulin-like receptor / Basic-leucine zipper (bZIP) domain signature. / Basic-leucine zipper (bZIP) domain profile. / basic region leucin zipper / Basic-leucine zipper domain / Basic-leucine zipper domain superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Alpha-Beta Horseshoe / 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 / 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 / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Insulin-like growth factor 2 / General control transcription factor GCN4 / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Saccharomyces cerevisiae (brewer's yeast)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsXu, Y. / Kirk, N.S. / Lawrence, M.C. / Croll, T.I.
Funding support Australia, United Kingdom, 2items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1128553 Australia
Wellcome Trust209407/Z/17/ United Kingdom
CitationJournal: Structure / Year: 2020
Title: How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor.
Authors: Yibin Xu / Nicholas S Kirk / Hariprasad Venugopal / Mai B Margetts / Tristan I Croll / Jarrod J Sandow / Andrew I Webb / Carlie A Delaine / Briony E Forbes / Michael C Lawrence /
Abstract: Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth ...Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth factor II signaling via IGF-1R, despite the affinity of insulin-like growth factor II for IGF-1R being within an order of magnitude of that of insulin-like growth factor I. Here, we describe the cryoelectron microscopy structure of insulin-like growth factor II bound to a leucine-zipper-stabilized IGF-1R ectodomain, determined in two conformations to a maximum average resolution of 3.2 Å. The two conformations differ in the relative separation of their respective points of membrane entry, and comparison with the structure of insulin-like growth factor I bound to IGF-1R reveals long-suspected differences in the way in which the critical C domain of the respective growth factors interact with IGF-1R.
History
DepositionFeb 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2020Provider: repository / Type: Initial release
Revision 1.1May 20, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Jul 15, 2020Group: Database references / Category: citation
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jul 22, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _entity.pdbx_description ..._chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Oct 9, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Leucine-zippered human type 1 insulin-like growth factor receptor ectodomain
B: Leucine-zippered human type 1 insulin-like growth factor receptor ectodomain
I: Insulin-like growth factor II
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,2447
Polymers225,3593
Non-polymers8854
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, All components were present in the map
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6140 Å2
ΔGint-7 kcal/mol
Surface area39510 Å2

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Components

#1: Protein Leucine-zippered human type 1 insulin-like growth factor receptor ectodomain / Insulin-like growth factor I receptor / IGF-I receptor / Amino acid biosynthesis regulatory protein


Mass: 108937.242 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Gene: IGF1R, GCN4, AAS3, ARG9, YEL009C / Plasmid: pEE14 / Strain: ATCC 204508 / S288c / Cell line (production host): CHO-K1 / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P08069, UniProt: P03069, receptor protein-tyrosine kinase
#2: Protein Insulin-like growth factor II / IGF-II / Somatomedin-A / T3M-11-derived growth factor


Mass: 7484.472 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGF2, PP1446 / Production host: Escherichia coli (E. coli) / References: UniProt: P01344
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
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

Component
IDNameTypeEntity IDParent-IDSource
1Head region of the close-leg conformation of the human type 1 insulin-like growth factor receptor ectodomain in complex with human insulin-like growth factor II.COMPLEX#1-#20MULTIPLE SOURCES
2Insulin-like growth factor 1 receptorCOMPLEX#11RECOMBINANT
3Insulin-like growth factor IICOMPLEX#21RECOMBINANT
Molecular weightValue: 0.25 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
22Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCellPlasmid
11Cricetulus griseus (Chinese hamster)10029CHO-K1pEE14
22Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
Buffer component
IDConc.FormulaBuffer-ID
124.8 mMTris-HCl1
2137 mMNaCl1
32.7 mMKCl1
40.02 %NaN31
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: IGFII:IGF-1R molar ratio 1.5:1
Specimen supportDetails: 15mA current / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil, UltrAuFoil, R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 10 sec. / Electron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4585
EM imaging opticsEnergyfilter name: GIF Quantum LS
Image scansMovie frames/image: 50 / Used frames/image: 1-50

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameVersionCategoryDetails
1RELION3.0.5particle selectiontemplate picking
2EPUimage acquisition
4CTFFIND4.1.13CTF correction
9PHENIX1.16model refinement
10cryoSPARC2.11initial Euler assignment
11cryoSPARC2.11final Euler assignment
12cryoSPARC2.11classification
13cryoSPARC2.113D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2057701
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 108899 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Details: UCSF Chimera was used for the initial fitting and ISOLDE v 1.03b was using for flexible fitting.
Atomic model buildingPDB-ID: 5U8R

5u8r


Accession code: 5U8R / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00512940
ELECTRON MICROSCOPYf_angle_d0.73923323
ELECTRON MICROSCOPYf_dihedral_angle_d18.2155237
ELECTRON MICROSCOPYf_chiral_restr0.05991
ELECTRON MICROSCOPYf_plane_restr0.0061910

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