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- EMDB-9838: Cryo-EM structure of the full-length human IGF-1R in complex with... -

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Basic information

Entry
Database: EMDB / ID: EMD-9838
TitleCryo-EM structure of the full-length human IGF-1R in complex with insulin
Map data
Sample
  • Complex: complex of full-length human type 1 insulin-like growth factor receptor with insulin
    • Protein or peptide: Insulin
  • Protein or peptide: Insulin-like growth factor 1 receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


cardiac atrium development / negative regulation of cholangiocyte apoptotic process / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / protein kinase complex / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / insulin-like growth factor binding / negative regulation of muscle cell apoptotic process ...cardiac atrium development / negative regulation of cholangiocyte apoptotic process / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / protein kinase complex / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / insulin-like growth factor binding / negative regulation of muscle cell apoptotic process / cellular response to progesterone stimulus / positive regulation of DNA metabolic process / cellular response to zinc ion starvation / cellular response to aldosterone / insulin receptor complex / cellular response to testosterone stimulus / negative regulation of hepatocyte apoptotic process / insulin-like growth factor I binding / insulin receptor activity / transcytosis / alphav-beta3 integrin-IGF-1-IGF1R complex / response to alkaloid / positive regulation of protein-containing complex disassembly / cellular response to angiotensin / cellular response to insulin-like growth factor stimulus / dendritic spine maintenance / response to L-glutamate / insulin binding / negative regulation of NAD(P)H oxidase activity / establishment of cell polarity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / negative regulation of MAPK cascade / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / Insulin processing / negative regulation of fatty acid metabolic process / positive regulation of axon regeneration / negative regulation of feeding behavior / amyloid-beta clearance / regulation of protein secretion / positive regulation of cytokinesis / positive regulation of osteoblast proliferation / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / Regulation of gene expression in beta cells / regulation of JNK cascade / negative regulation of acute inflammatory response / estrous cycle / alpha-beta T cell activation / negative regulation of respiratory burst involved in inflammatory response / insulin receptor substrate binding / G-protein alpha-subunit binding / response to vitamin E / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / SHC-related events triggered by IGF1R / negative regulation of protein secretion / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / positive regulation of nitric oxide mediated signal transduction / fatty acid homeostasis / regulation of protein localization to plasma membrane / phosphatidylinositol 3-kinase binding / COPI-mediated anterograde transport / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / peptidyl-tyrosine autophosphorylation / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / cellular response to transforming growth factor beta stimulus / T-tubule / Insulin receptor recycling / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / endoplasmic reticulum-Golgi intermediate compartment membrane / neuron projection maintenance / activation of protein kinase B activity / cellular response to dexamethasone stimulus / cerebellum development / positive regulation of glycolytic process / axonogenesis / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / insulin-like growth factor receptor signaling pathway / response to nicotine / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / Regulation of insulin secretion / positive regulation of long-term synaptic potentiation / caveola / endosome lumen
Similarity search - Function
Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. ...Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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 / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.0 Å
AuthorsZhang X / Yu D / Wang T
Funding support China, 3 items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2018YFA0507103 China
National Natural Science Foundation of China11774011 China
National Natural Science Foundation of China31870719 China
CitationJournal: Structure / Year: 2020
Title: Visualization of Ligand-Bound Ectodomain Assembly in the Full-Length Human IGF-1 Receptor by Cryo-EM Single-Particle Analysis.
Authors: Xi Zhang / Daqi Yu / Jingchuan Sun / Yujie Wu / Junyuan Gong / Xuemei Li / Li Liu / Shan Liu / Jianbo Liu / Yulan Wu / Dongyang Li / Yinping Ma / Xu Han / Yanan Zhu / Zhaolong Wu / Yihua ...Authors: Xi Zhang / Daqi Yu / Jingchuan Sun / Yujie Wu / Junyuan Gong / Xuemei Li / Li Liu / Shan Liu / Jianbo Liu / Yulan Wu / Dongyang Li / Yinping Ma / Xu Han / Yanan Zhu / Zhaolong Wu / Yihua Wang / Qi Ouyang / Tao Wang /
Abstract: Tyrosine kinase receptor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) bind to hormones, such as insulin, IGF-1, and IGF-2, and transduces the signals across the cell ...Tyrosine kinase receptor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) bind to hormones, such as insulin, IGF-1, and IGF-2, and transduces the signals across the cell membrane. However, the complete structure of the receptor and the signal transduction mechanism remains unclear. Here, we report the cryo-EM structure of the ligand-bound ectodomain in the full-length human IGF-1R. We reconstructed the IGF-1R/insulin complex at 4.7 Å and the IGF-1R/IGF-1 complex at 7.7 Å. Our structures reveal that only one insulin or one IGF-1 molecule binds to and activates the full-length human IGF-1R receptor.
History
DepositionFeb 27, 2019-
Header (metadata) releaseJan 1, 2020-
Map releaseMar 4, 2020-
UpdateJul 29, 2020-
Current statusJul 29, 2020Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6jk8
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9838.png

Downloads & links

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Map

FileDownload / File: emd_9838.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.37 Å
Density
Contour LevelBy AUTHOR: 0.021 / Movie #1: 0.021
Minimum - Maximum-0.070980266 - 0.10052515
Average (Standard dev.)0.00059106766 (±0.0039826473)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 219.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.371.371.37
M x/y/z160160160
origin x/y/z0.0000.0000.000
length x/y/z219.200219.200219.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ512512512
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS160160160
D min/max/mean-0.0710.1010.001

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Supplemental data

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Sample components

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Entire : complex of full-length human type 1 insulin-like growth factor re...

EntireName: complex of full-length human type 1 insulin-like growth factor receptor with insulin
Components
  • Complex: complex of full-length human type 1 insulin-like growth factor receptor with insulin
    • Protein or peptide: Insulin
  • Protein or peptide: Insulin-like growth factor 1 receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: complex of full-length human type 1 insulin-like growth factor re...

SupramoleculeName: complex of full-length human type 1 insulin-like growth factor receptor with insulin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293T
Molecular weightExperimental: 310 KDa

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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: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 154.964469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKSGSGGGSP TSLWGLLFLS AALSLWPTSG EICGPGIDIR NDYQQLKRLE NCTVIEGYLH ILLISKAEDY RSYRFPKLTV ITEYLLLFR VAGLESLGDL FPNLTVIRGW KLFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTVDWSL I LDAVSNNY ...String:
MKSGSGGGSP TSLWGLLFLS AALSLWPTSG EICGPGIDIR NDYQQLKRLE NCTVIEGYLH ILLISKAEDY RSYRFPKLTV ITEYLLLFR VAGLESLGDL FPNLTVIRGW KLFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTVDWSL I LDAVSNNY IVGNKPPKEC GDLCPGTMEE KPMCEKTTIN NEYNYRCWTT NRCQKMCPST CGKRACTENN ECCHPECLGS CS APDNDTA CVACRHYYYA GVCVPACPPN TYRFEGWRCV DRDFCANILS AESSDSEGFV IHDGECMQEC PSGFIRNGSQ SMY CIPCEG PCPKVCEEEK KTKTIDSVTS AQMLQGCTIF KGNLLINIRR GNNIASELEN FMGLIEVVTG YVKIRHSHAL VSLS FLKNL RLILGEEQLE GNYSFYVLDN QNLQQLWDWD HRNLTIKAGK MYFAFNPKLC VSEIYRMEEV TGTKGRQSKG DINTR NNGE RASCESDVLH FTSTTTSKNR IIITWHRYRP PDYRDLISFT VYYKEAPFKN VTEYDGQDAC GSNSWNMVDV DLPPNK DVE PGILLHGLKP WTQYAVYVKA VTLTMVENDH IRGAKSEILY IRTNASVPSI PLDVLSASNS SSQLIVKWNP PSLPNGN LS YYIVRWQRQP QDGYLYRHNY CSKDKIPIRK YADGTIDIEE VTENPKTEVC GGEKGPCCAC PKTEAEKQAE KEEAEYRK V FENFLHNSIF VPRPERKRRD VMQVANTTMS SRSRNTTAAD TYNITDPEEL ETEYPFFESR VDNKERTVIS NLRPFTLYR IDIHSCNHEA EKLGCSASNF VFARTMPAEG ADDIPGPVTW EPRPENSIFL KWPEPENPNG LILMYEIKYG SQVEDQRECV SRQEYRKYG GAKLNRLNPG NYTARIQATS LSGNGSWTDP VFFYVQAKTG YENFIHLIIA LPVAVLLIVG GLVIMLYVFH R KRNNSRLG NGVLYASVNP EYFSAADVYV PDEWEVAREK ITMSRELGQG SFGMVYEGVA KGVVKDEPET RVAIKTVNEA AS MRERIEF LNEASVMKEF NCHHVVRLLG VVSQGQPTLV IMELMTRGDL KSYLRSLRPE MENNPVLAPP SLSKMIQMAG EIA DGMAYL NANKFVHRDL AARNCMVAED FTVKIGDFGM TRDIYETDYY RKGGKGLLPV RWMSPESLKD GVFTTYSDVW SFGV VLWEI ATLAEQPYQG LSNEQVLRFV MEGGLLDKPD NCPDMLFELM RMCWQYNPKM RPSFLEIISS IKEEMEPGFR EVSFY YSEE NKLPEPEELD LEPENMESVP LDPSASSSSL PLPDRHSGHK AENGPGPGVL VLRASFDERQ PYAHMNGGRK NERALP LPQ SSTC

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Macromolecule #2: Insulin

MacromoleculeName: Insulin / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.989862 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MALWMRLLPL LALLALWGPD PAAAFVNQHL CGSHLVEALY LVCGERGFFY TPKTRREAED LQVGQVELGG GPGAGSLQPL ALEGSLQKR GIVEQCCTSI CSLYQLENYC N

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration2 mg/mL
BufferpH: 7.4 / Details: PBS with detergent
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV
Detailshuman type 1 insulin-like growth factor receptor saturated with human insulin

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 36496 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal magnification: 105000
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: Gctf
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5u8q


Details: the ECD domain of IGF-1R
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0.4) / Number images used: 301139
FSC plot (resolution estimation)

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