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- EMDB-24791: Head region of a complex of IGF-I with the ectodomain of a hybrid... -

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Entry
Database: EMDB / ID: EMD-24791
TitleHead region of a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor
Map dataHead region of a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor
Sample
  • Complex: a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor
    • Protein or peptide: Insulin-like growth factor 1 receptor
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin-like growth factor I
  • Ligand: beta-D-mannopyranose
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsinsulin receptor / type 1 insulin like growth factor receptor / hybrid receptor / insulin like growth factor I / leucine zipper / cryo electron microscopy / SIGNALING PROTEIN
Function / homology
Function and homology information


glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / positive regulation of trophectodermal cell proliferation / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex / positive regulation of glycoprotein biosynthetic process / cardiac atrium development / negative regulation of cholangiocyte apoptotic process / proteoglycan biosynthetic process ...glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / positive regulation of trophectodermal cell proliferation / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex / positive regulation of glycoprotein biosynthetic process / cardiac atrium development / negative regulation of cholangiocyte apoptotic process / proteoglycan biosynthetic process / positive regulation of steroid hormone biosynthetic process / protein kinase complex / myotube cell development / negative regulation of neuroinflammatory response / positive regulation of transcription regulatory region DNA binding / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / protein transporter activity / bone mineralization involved in bone maturation / positive regulation of cell growth involved in cardiac muscle cell development / IRS-related events triggered by IGF1R / negative regulation of vascular associated smooth muscle cell apoptotic process / negative regulation of muscle cell apoptotic process / exocytic vesicle / cellular response to progesterone stimulus / positive regulation of DNA metabolic process / regulation of female gonad development / positive regulation of meiotic cell cycle / cellular response to zinc ion starvation / insulin-like growth factor II binding / cell activation / positive regulation of developmental growth / cellular response to aldosterone / positive regulation of calcineurin-NFAT signaling cascade / male sex determination / cellular response to testosterone stimulus / insulin receptor complex / transmembrane receptor protein tyrosine kinase activator activity / transcytosis / insulin-like growth factor I binding / negative regulation of hepatocyte apoptotic process / exocrine pancreas development / positive regulation of protein-containing complex disassembly / alphav-beta3 integrin-IGF-1-IGF1R complex / response to alkaloid / cell surface receptor signaling pathway via STAT / myoblast differentiation / positive regulation of Ras protein signal transduction / regulation of JNK cascade / positive regulation of insulin-like growth factor receptor signaling pathway / dendritic spine maintenance / myoblast proliferation / cargo receptor activity / insulin binding / growth hormone receptor signaling pathway / negative regulation of interleukin-1 beta production / positive regulation of DNA binding / neuronal cell body membrane / adrenal gland development / PTB domain binding / cellular response to insulin-like growth factor stimulus / muscle organ development / response to L-glutamate / Signaling by Insulin receptor / positive regulation of smooth muscle cell migration / IRS activation / establishment of cell polarity / positive regulation of axon regeneration / positive regulation of cardiac muscle hypertrophy / negative regulation of release of cytochrome c from mitochondria / positive regulation of osteoblast proliferation / negative regulation of amyloid-beta formation / positive regulation of cytokinesis / negative regulation of smooth muscle cell apoptotic process / positive regulation of activated T cell proliferation / positive regulation of respiratory burst / amyloid-beta clearance / Respiratory syncytial virus (RSV) attachment and entry / regulation of embryonic development / positive regulation of receptor internalization / protein kinase activator activity / insulin receptor substrate binding / negative regulation of tumor necrosis factor production / cellular response to angiotensin / response to vitamin E / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / G-protein alpha-subunit binding / epithelial to mesenchymal transition / negative regulation of MAPK cascade / positive regulation of glycogen biosynthetic process / Signal attenuation / SHC-related events triggered by IGF1R / phosphatidylinositol 3-kinase binding / positive regulation of osteoblast differentiation / transport across blood-brain barrier / peptidyl-tyrosine autophosphorylation / heart morphogenesis / activation of protein kinase B activity
Similarity search - Function
Insulin-like growth factor I / Insulin-like growth factor / 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 family / Insulin-like / Insulin/IGF/Relaxin family ...Insulin-like growth factor I / Insulin-like growth factor / 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 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-like growth factor 1 / Insulin receptor / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsXu Y / Lawrence MC
Funding support Australia, 1 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1128553 Australia
CitationJournal: Structure / Year: 2022
Title: How insulin-like growth factor I binds to a hybrid insulin receptor type 1 insulin-like growth factor receptor.
Authors: Yibin Xu / Mai B Margetts / Hari Venugopal / John G Menting / Nicholas S Kirk / Tristan I Croll / Carlie Delaine / Briony E Forbes / Michael C Lawrence /
Abstract: Monomers of the insulin receptor and type 1 insulin-like growth factor receptor (IGF-1R) can combine stochastically to form heterodimeric hybrid receptors. These hybrid receptors display ligand ...Monomers of the insulin receptor and type 1 insulin-like growth factor receptor (IGF-1R) can combine stochastically to form heterodimeric hybrid receptors. These hybrid receptors display ligand binding and signaling properties that differ from those of the homodimeric receptors. Here, we describe the cryoelectron microscopy structure of such a hybrid receptor in complex with insulin-like growth factor I (IGF-I). The structure (ca. 3.7 Å resolution) displays a single IGF-I ligand, bound in a similar fashion to that seen for IGFs in complex with IGF-1R. The IGF-I ligand engages the first leucine-rich-repeat domain and cysteine-rich region of the IGF-1R monomer (rather than those of the insulin receptor monomer), consistent with the determinants for IGF binding residing in the IGF-1R cysteine-rich region. The structure broadens our understanding of this receptor family and assists in delineating the key structural motifs involved in binding their respective ligands.
History
DepositionAug 30, 2021-
Header (metadata) releaseJul 6, 2022-
Map releaseJul 6, 2022-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_24791.png

Downloads & links

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Map

FileDownload / File: emd_24791.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHead region of a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor
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: 0.1529
Minimum - Maximum-0.14116551 - 1.0610286
Average (Standard dev.)-0.00021748828 (±0.0117808785)
SymmetrySpace group: 1
Details

EMDB XML:

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

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Supplemental data

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Sample components

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Entire : a complex of IGF-I with the ectodomain of a hybrid insulin recept...

EntireName: a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor
Components
  • Complex: a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor
    • Protein or peptide: Insulin-like growth factor 1 receptor
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin-like growth factor I
  • Ligand: beta-D-mannopyranose
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: a complex of IGF-I with the ectodomain of a hybrid insulin recept...

SupramoleculeName: a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 250 kDa/nm

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Macromolecule #1: Insulin-like growth factor 1 receptor

MacromoleculeName: Insulin-like growth factor 1 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
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

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Macromolecule #2: Insulin receptor

MacromoleculeName: Insulin receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 109.809617 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDIC P GTAKGKTN ...String:
HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDIC P GTAKGKTN CPATVINGQF VERCWTHSHC QKVCPTICKS HGCTAEGLCC HSECLGNCSQ PDDPTKCVAC RNFYLDGRCV ET CPPPYYH FQDWRCVNFS FCQDLHHKCK NSRRQGCHQY VIHNNKCIPE CPSGYTMNSS NLLCTPCLGP CPKVCHLLEG EKT IDSVTS AQELRGCTVI NGSLIINIRG GNNLAAELEA NLGLIEEISG YLKIRRSYAL VSLSFFRKLR LIRGETLEIG NYSF YALDN QNLRQLWDWS KHNLTITQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDQ ASCENELLKF SYIRT SFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN VTEFDGQDAC GSNSWTVVDI DPPLRSNDPK SQNHPGWLMR GLKPWT QYA IFVKTLVTFS DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSE LF ELDYCLKGLK LPSRTWSPPF ESEDSQKHNQ SEYEDSAGEC CSCPKTDSQI LKELEESSFR KTFEDYLHNV VFVPRKTS S GTGAEDPRPS RKRRSLGDVG NVTVAVPTVA AFPNTSSTSV PTSPEEHRPF EKVVNKESLV ISGLRHFTGY RIELQACNQ DTPEERCSVA AYVSARTMPE AKADDIVGPV THEIFENNVV HLMWQEPKEP NGLIVLYEVS YRRYGDEELH LCVSRKHFAL ERGCRLRGL SPGNYSVRIR ATSLAGNGSW TEPTYFYVTD YLDVPSNIAR MKQLEDKVEE LLSKNYHLEN EVARLKKLVG E R

UniProtKB: Insulin receptor

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Macromolecule #3: Insulin-like growth factor I

MacromoleculeName: Insulin-like growth factor I / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.663752 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GPETLCGAEL VDALQFVCGD RGFYFNKPTG YGSSSRRAPQ TGIVDECCFR SCDLRRLEMY CAPLKPAKSA

UniProtKB: Insulin-like growth factor 1

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Macromolecule #6: beta-D-mannopyranose

MacromoleculeName: beta-D-mannopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: BMA
Molecular weightTheoretical: 180.156 Da
Chemical component information

ChemComp-BMA:
beta-D-mannopyranose

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 7 / 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

BufferpH: 8 / Component - Concentration: 20.0 mM / Component - Formula: C4H11NO3 / Component - Name: TRIS / Details: 20mM Tris pH 8.0 160mM NaCl
GridMaterial: COPPER / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV
Details0.2mg/ml

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 1.44 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
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. 2.15.0) / Number images used: 151240
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 2.15.0)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7s0q:
Head region of a complex of IGF-I with the ectodomain of a hybrid insulin receptor / type 1 insulin-like growth factor receptor

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