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Entry
Database: EMDB / ID: EMD-21417
TitleHead region of the close conformation of the human type 1 insulin-like growth factor receptor ectodomain in complex with human insulin-like growth factor II.
Map dataHead region of the close conformation of the human type 1 insulin-like growth factor receptor ectodomain in complex with human insulin-like growth factor II
Sample
  • Complex: Head 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: Insulin-like growth factor 1 receptor
      • Protein or peptide: Leucine-zippered human type 1 insulin-like growth factor receptor ectodomain
    • Complex: Insulin-like growth factor II
      • Protein or peptide: Insulin-like growth factor II
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsType 1 insulin-like growth factor receptor / Insulin-like growth factor II / ectodomain receptor / tyrosine kinase / SIGNALING PROTEIN
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 / regulation of muscle cell differentiation / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / transcytosis ...embryonic placenta morphogenesis / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / protein kinase complex / regulation of muscle cell differentiation / insulin-like growth factor binding / 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 / positive regulation of organ growth / Activation of the AP-1 family of transcription factors / 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 / insulin receptor complex / genomic imprinting / transmembrane receptor protein tyrosine kinase activator activity / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / positive regulation of multicellular organism growth / exocrine pancreas development / Oxidative Stress Induced Senescence / alphav-beta3 integrin-IGF-1-IGF1R complex / regulation of JNK cascade / dendritic spine maintenance / positive regulation of vascular endothelial cell proliferation / insulin binding / amyloid-beta clearance / positive regulation of activated T cell proliferation / TFIID-class transcription factor complex binding / amino acid biosynthetic process / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of cell division / insulin receptor substrate binding / insulin-like growth factor receptor activity / positive regulation of RNA polymerase II transcription preinitiation complex assembly / peptidyl-tyrosine autophosphorylation / 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 / insulin receptor activity / 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 / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / protein serine/threonine kinase activator activity / animal organ morphogenesis / insulin receptor binding / cellular response to glucose stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / growth factor activity / receptor protein-tyrosine kinase / hormone activity / RNA polymerase II transcription regulator complex / glucose metabolic process / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / osteoblast differentiation / integrin binding / 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 / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / in utero embryonic development / DNA-binding transcription factor activity, RNA polymerase II-specific / Extra-nuclear estrogen signaling / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / intracellular signal transduction / immune response / cilium / positive regulation of cell migration / receptor ligand activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / 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 growth factor / : / 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 ...Insulin-like growth factor II E-peptide, C-terminal / Insulin-like growth factor II / Insulin-like growth factor II E-peptide / Insulin-like growth factor / : / 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. / 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
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 (strain ATCC 204508 / S288c) (yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsXu Y / Kirk NS
Funding support Australia, United Kingdom, 2 items
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, 2020-
Header (metadata) releaseMay 13, 2020-
Map releaseMay 13, 2020-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.5
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  • Surface view with fitted model
  • Atomic models: PDB-6vwi
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6vwi
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21417.png

Downloads & links

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Map

FileDownload / File: emd_21417.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHead region of the close conformation of the human type 1 insulin-like growth factor receptor ectodomain in complex with human insulin-like growth factor II
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 400 pix.
= 424. Å		1.06 Å/pix.
x 400 pix.
= 424. Å		1.06 Å/pix.
x 400 pix.
= 424. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5 / Movie #1: 0.5
Minimum - Maximum-0.8693394 - 2.312179
Average (Standard dev.)0.0010262777 (±0.03197206)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 423.99997 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z424.000424.000424.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.8692.3120.001

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Supplemental data

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Sample components

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Entire : Head region of the close-leg conformation of the human type 1 ins...

EntireName: Head 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.
Components
  • Complex: Head 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: Insulin-like growth factor 1 receptor
      • Protein or peptide: Leucine-zippered human type 1 insulin-like growth factor receptor ectodomain
    • Complex: Insulin-like growth factor II
      • Protein or peptide: Insulin-like growth factor II
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Head region of the close-leg conformation of the human type 1 ins...

SupramoleculeName: Head 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.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 250 KDa

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Supramolecule #2: Insulin-like growth factor 1 receptor

SupramoleculeName: Insulin-like growth factor 1 receptor / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Insulin-like growth factor II

SupramoleculeName: Insulin-like growth factor II / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: Leucine-zippered human type 1 insulin-like growth factor receptor...

MacromoleculeName: Leucine-zippered human type 1 insulin-like growth factor receptor ectodomain
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c
Molecular weightTheoretical: 108.937242 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EICGPGIDIR NDYQQLKRLE NCTVIEGYLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTVDWSL ILDAVSNNYI VGNKPPKECG DLCPGTMEEK P MCEKTTIN ...String:
EICGPGIDIR NDYQQLKRLE NCTVIEGYLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTVDWSL ILDAVSNNYI VGNKPPKECG DLCPGTMEEK P MCEKTTIN NEYNYRCWTT NRCQKMCPST CGKRACTENN ECCHPECLGS CSAPDNDTAC VACRHYYYAG VCVPACPPNT YR FEGWRCV DRDFCANILS AESSDSEGFV IHDGECMQEC PSGFIRNGSQ SMYCIPCEGP CPKVCEEEKK TKTIDSVTSA QML QGCTIF KGNLLINIRR GNNIASELEN FMGLIEVVTG YVKIRHSHAL VSLSFLKNLR LILGEEQLEG NYSFYVLDNQ NLQQ LWDWD HRNLTIKAGK MYFAFNPKLC VSEIYRMEEV TGTKGRQSKG DINTRNNGER ASCESDVLHF TSTTTSKNRI IITWH RYRP PDYRDLISFT VYYKEAPFKN VTEYDGQDAC GSNSWNMVDV DLPPNKDVEP GILLHGLKPW TQYAVYVKAV TLTMVE NDH IRGAKSEILY IRTNASVPSI PLDVLSASNS SSQLIVKWNP PSLPNGNLSY YIVRWQRQPQ DGYLYRHNYC SKDKIPI RK YADGTIDIEE VTENPKTEVC GGEKGPCCAC PKTEAEKQAE KEEAEYRKVF ENFLHNSIFV PRPERKRRDV MQVANTTM S SRSRNTTAAD TYNITDPEEL ETEYPFFESR VDNKERTVIS NLRPFTLYRI DIHSCNHEAE KLGCSASNFV FARTMPAEG ADDIPGPVTW EPRPENSIFL KWPEPENPNG LILMYEIKYG SQVEDQRECV SRQEYRKYGG AKLNRLNPGN YTARIQATSL SGNGSWTDP VFFYVQAKTG YENFIHRMKQ LEDKVEELLS KNYHLENEVA RLKKLVGERS SSEQKLISEE DLN

UniProtKB: Insulin-like growth factor 1 receptor, General control transcription factor GCN4

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Macromolecule #2: Insulin-like growth factor II

MacromoleculeName: Insulin-like growth factor II / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.484472 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
AYRPSETLCG GELVDTLQFV CGDRGFYFSR PASRVSRRSR GIVEECCFRS CDLALLETYC ATPAKSE

UniProtKB: Insulin-like growth factor 2

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.1 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormula
24.8 mMTris-HCl
137.0 mMNaCl
2.7 mMKCl
0.02 %NaN3
GridModel: Quantifoil, UltrAuFoil, R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Details: 15mA current
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsIGFII:IGF-1R molar ratio 1.5:1

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 4585 / Average exposure time: 10.0 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2057701
Startup modelType of model: OTHER
Details: Initial model was of the same ectodomain construct in complex with IGF-I (unpublished data).
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.11) / Number images used: 108899
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.11)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.11)
Final 3D classificationNumber classes: 7 / Software - Name: cryoSPARC (ver. 2.11)

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Atomic model buiding 1

Initial modelPDB ID:

5u8r


Chain - Source name: PDB / Chain - Initial model type: experimental model
DetailsUCSF Chimera was used for the initial fitting and ISOLDE v 1.03b was using for flexible fitting.
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6vwi:
Head 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.

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