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Yorodumi- EMDB-28693: Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutan... -
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-Basic information
Entry | Database: EMDB / ID: EMD-28693 | |||||||||
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Title | Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation | |||||||||
Map data | Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation | |||||||||
Sample |
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Function / homology | Function and homology information Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / mitotic nuclear division / 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 ...Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / mitotic nuclear division / 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 / proteoglycan biosynthetic process / negative regulation of cholangiocyte apoptotic process / positive regulation of glycoprotein biosynthetic process / myotube cell development / negative regulation of vascular associated smooth muscle cell apoptotic process / Extra-nuclear estrogen signaling / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / bone mineralization involved in bone maturation / negative regulation of neuroinflammatory response / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / insulin-like growth factor binding / IRS-related events triggered by IGF1R / positive regulation of cell growth involved in cardiac muscle cell development / exocytic vesicle / negative regulation of muscle cell apoptotic process / positive regulation of meiotic cell cycle / positive regulation of transcription regulatory region DNA binding / positive regulation of DNA metabolic process / positive regulation of developmental growth / mammary gland development / cell activation / positive regulation of calcineurin-NFAT signaling cascade / male sex determination / exocrine pancreas development / prostate gland epithelium morphogenesis / insulin receptor complex / negative regulation of hepatocyte apoptotic process / insulin receptor activity / alphav-beta3 integrin-IGF-1-IGF1R complex / positive regulation of Ras protein signal transduction / positive regulation of protein-containing complex disassembly / myoblast differentiation / positive regulation of insulin-like growth factor receptor signaling pathway / myoblast proliferation / dendritic spine maintenance / muscle organ development / negative regulation of interleukin-1 beta production / response to L-glutamate / adrenal gland development / cellular response to insulin-like growth factor stimulus / positive regulation of DNA binding / establishment of cell polarity / postsynaptic modulation of chemical synaptic transmission / positive regulation of cytokinesis / negative regulation of release of cytochrome c from mitochondria / positive regulation of axon regeneration / positive regulation of cardiac muscle hypertrophy / positive regulation of smooth muscle cell migration / positive regulation of activated T cell proliferation / positive regulation of osteoblast proliferation / negative regulation of amyloid-beta formation / negative regulation of smooth muscle cell apoptotic process / regulation of JNK cascade / negative regulation of tumor necrosis factor production / insulin receptor substrate binding / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / epithelial to mesenchymal transition / positive regulation of glycogen biosynthetic process / epidermis development / Synthesis, secretion, and deacylation of Ghrelin / G-protein alpha-subunit binding / estrous cycle / negative regulation of MAPK cascade / SHC-related events triggered by IGF1R / positive regulation of osteoblast differentiation / phosphatidylinositol 3-kinase binding / positive regulation of tyrosine phosphorylation of STAT protein / cellular response to transforming growth factor beta stimulus / positive regulation of vascular associated smooth muscle cell proliferation / insulin-like growth factor receptor binding / T-tubule / activation of protein kinase B activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of glycolytic process / axonogenesis / positive regulation of mitotic nuclear division / cerebellum development / positive regulation of epithelial cell proliferation / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / skeletal system development / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of D-glucose import / positive regulation of protein secretion / animal organ morphogenesis / cellular response to glucose stimulus / positive regulation of smooth muscle cell proliferation / insulin receptor binding Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) / Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.0 Å | |||||||||
Authors | Li J / Wu JY / Hall C / Bai XC / Choi E | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Elife / Year: 2022 Title: Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor. Authors: Jie Li / Jiayi Wu / Catherine Hall / Xiao-Chen Bai / Eunhee Choi / Abstract: The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked ...The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the -shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a -shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the -shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_28693.map.gz | 110.5 MB | EMDB map data format | |
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Header (meta data) | emd-28693-v30.xml emd-28693.xml | 18.7 KB 18.7 KB | Display Display | EMDB header |
Images | emd_28693.png | 35.6 KB | ||
Others | emd_28693_half_map_1.map.gz emd_28693_half_map_2.map.gz | 139.2 MB 139.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-28693 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-28693 | HTTPS FTP |
-Validation report
Summary document | emd_28693_validation.pdf.gz | 692.6 KB | Display | EMDB validaton report |
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Full document | emd_28693_full_validation.pdf.gz | 692.1 KB | Display | |
Data in XML | emd_28693_validation.xml.gz | 14.5 KB | Display | |
Data in CIF | emd_28693_validation.cif.gz | 17 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28693 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28693 | HTTPS FTP |
-Related structure data
Related structure data | 8eyrMC 8eyxC 8eyyC 8ez0C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_28693.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.83 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Cryo-EM structure of two IGF1 bound full-length mouse...
File | emd_28693_half_map_1.map | ||||||||||||
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Annotation | Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation Unfiltered half1 map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Cryo-EM structure of two IGF1 bound full-length mouse...
File | emd_28693_half_map_2.map | ||||||||||||
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Annotation | Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation Unfiltered half2 map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Two IGF1 bound full-length mouse IGF1R mutant (four glycine resid...
Entire | Name: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation |
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Components |
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-Supramolecule #1: Two IGF1 bound full-length mouse IGF1R mutant (four glycine resid...
Supramolecule | Name: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Mus musculus (house mouse) |
-Macromolecule #1: Insulin-like growth factor 1 receptor
Macromolecule | Name: Insulin-like growth factor 1 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 144.481953 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: EICGPGIDIR NDYQQLKRLE NCTVIEGFLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTIDWSL ILDAVSNNYI VGNKPPKECG DLCPGTLEEK P MCEKTTIN ...String: EICGPGIDIR NDYQQLKRLE NCTVIEGFLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTIDWSL ILDAVSNNYI VGNKPPKECG DLCPGTLEEK P MCEKTTIN NEYNYRCWTT NRCQKMCPSV CGKRACTENN ECCHPECLGS CHTPDDNTTC VACRHYYYKG VCVPACPPGT YR FEGWRCV DRDFCANIPN AESSDSDGFV IHDDECMQEC PSGFIRNSTQ SMYCIPCEGP CPKVCGDEEK KTKTIDSVTS AQM LQGCTI LKGNLLINIR RGNNIASELE NFMGLIEVVT GYVKIRHSHA LVSLSFLKNL RLILGEEQLE GNYSFYVLDN QNLQ QLWDW NHRNLTVRSG KMYFAFNPKL CVSEIYRMEE VTGTKGRQSK GDINTRNNGE RASCESDVLR FTSTTTWKNR IIITW HRYR PPDYRDLISF TVYYKEAPFK NVTEYDGQDA CGSNSWNMVD VDLPPNKEGE PGILLHGLKP WTQYAVYVKA VTLTMV END HIRGAKSEIL YIRTNASVPS IPLDVLSASN SSSQLIVKWN PPTLPNGNLS YYIVRWQRQP QDGYLYRHNY CSKDKIP IR KYADGTIDVE EVTENPKTEV CGGDKGPCCA CPGGGGKTEA EKQAEKEEAE YRKVFENFLH NSIFVPRPER RRRDVMQV A NTTMSSRSRN TTVADTYNIT DPEEFETEYP FFESRVDNKE RTVISNLRPF TLYRIDIHSC NHEAEKLGCS ASNFVFART MPAEGADDIP GPVTWEPRPE NSIFLKWPEP ENPNGLILMY EIKYGSQVED QRECVSRQEY RKYGGAKLNR LNPGNYTARI QATSLSGNG SWTDPVFFYV PAKTTYENFM HLIIALPVAI LLIVGGLVIM LYVFHRKRNN SRLGNGVLYA SVNPEYFSAA D VYVPDEWE VAREKITMNR ELGQGSFGMV YEGVAKGVVK DEPETRVAIK TVNEAASMRE RIEFLNEASV MKEFNCHHVV RL LGVVSQG QPTLVIMELM TRGDLKSYLR SLRPEVEQNN LVLIPPSLSK MIQMAGEIAD GMAYLNANKF VHRDLAARNC MVA EDFTVK IGDFGMTRDI YETDYYRKGG KGLLPVRWMS PESLKDGVFT THSDVWSFGV VLWEIATLAE QPYQGLSNEQ VLRF VMEGG LLDKPDNCPD MLFELMRMCW QYNPKMRPSF LEIIGSIKDE MEPSFQEVSF YYSEENKPPE P |
-Macromolecule #2: Insulin-like growth factor I
Macromolecule | Name: Insulin-like growth factor I / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 21.88132 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MGKISSLPTQ LFKCCFCDFL KVKMHTMSSS HLFYLALCLL TFTSSATAGP ETLCGAELVD ALQFVCGDRG FYFNKPTGYG SSSRRAPQT GIVDECCFRS CDLRRLEMYC APLKPAKSAR SVRAQRHTDM PKTQKYQPPS TNKNTKSQRR KGWPKTHPGG E QKEGTEAS ...String: MGKISSLPTQ LFKCCFCDFL KVKMHTMSSS HLFYLALCLL TFTSSATAGP ETLCGAELVD ALQFVCGDRG FYFNKPTGYG SSSRRAPQT GIVDECCFRS CDLRRLEMYC APLKPAKSAR SVRAQRHTDM PKTQKYQPPS TNKNTKSQRR KGWPKTHPGG E QKEGTEAS LQIRGKKKEQ RREIGSRNAE CRGKKGK |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 6 mg/mL |
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Buffer | pH: 7.4 |
Grid | Model: Quantifoil / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.6 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |