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Yorodumi- EMDB-41878: Cryo-EM structure of long form insulin receptor (IR-B) with four ... -
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-Basic information
Entry | Database: EMDB / ID: EMD-41878 | |||||||||
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Title | Cryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. | |||||||||
Map data | Cryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. | |||||||||
Sample |
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Keywords | Insulin receptor / IGF2 / RTK / SIGNALING PROTEIN | |||||||||
Function / homology | Function and homology information spongiotrophoblast cell proliferation / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / regulation of female gonad development / genomic imprinting / positive regulation of meiotic cell cycle ...spongiotrophoblast cell proliferation / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / regulation of female gonad development / genomic imprinting / positive regulation of meiotic cell cycle / positive regulation of organ growth / positive regulation of developmental growth / insulin-like growth factor II binding / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / positive regulation of multicellular organism growth / insulin receptor activity / positive regulation of protein-containing complex disassembly / cargo receptor activity / positive regulation of vascular endothelial cell proliferation / dendritic spine maintenance / insulin binding / PTB domain binding / neuronal cell body membrane / adrenal gland development / Signaling by Insulin receptor / IRS activation / positive regulation of activated T cell proliferation / transmembrane receptor protein tyrosine kinase activator activity / amyloid-beta clearance / activation of protein kinase activity / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / positive regulation of cell division / transport across blood-brain barrier / insulin receptor substrate binding / embryonic placenta development / epidermis development / positive regulation of glycogen biosynthetic process / SHC-related events triggered by IGF1R / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of insulin receptor signaling pathway / dendrite membrane / striated muscle cell differentiation / Insulin receptor recycling / insulin-like growth factor receptor binding / receptor-mediated endocytosis / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / protein serine/threonine kinase activator activity / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / learning / caveola / positive regulation of glucose import / animal organ morphogenesis / growth factor activity / positive regulation of MAP kinase activity / insulin receptor binding / hormone activity / receptor internalization / receptor protein-tyrosine kinase / memory / cellular response to growth factor stimulus / osteoblast differentiation / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / male gonad development / cell surface receptor protein tyrosine kinase signaling pathway / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / positive regulation of peptidyl-tyrosine phosphorylation / integrin binding / late endosome / glucose homeostasis / Platelet degranulation / insulin receptor signaling pathway / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / lysosome / receptor ligand activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / carbohydrate metabolic process / positive regulation of cell migration / positive regulation of protein phosphorylation Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
Authors | An W / Hall C / Li J / Huang A / Wu J / Park J / Bai XC / Choi E | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Nat Commun / Year: 2024 Title: Activation of the insulin receptor by insulin-like growth factor 2. Authors: Weidong An / Catherine Hall / Jie Li / Albert Hung / Jiayi Wu / Junhee Park / Liwei Wang / Xiao-Chen Bai / Eunhee Choi / Abstract: Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular ...Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_41878.map.gz | 102 MB | EMDB map data format | |
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Header (meta data) | emd-41878-v30.xml emd-41878.xml | 18.4 KB 18.4 KB | Display Display | EMDB header |
Images | emd_41878.png | 40.1 KB | ||
Filedesc metadata | emd-41878.cif.gz | 6.6 KB | ||
Others | emd_41878_half_map_1.map.gz emd_41878_half_map_2.map.gz | 140.1 MB 140.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-41878 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41878 | HTTPS FTP |
-Related structure data
Related structure data | 8u4cMC 8u4bC 8u4eC 8vjbC 8vjcC 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_41878.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 long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.08 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 long form insulin receptor (IR-B)...
File | emd_41878_half_map_1.map | ||||||||||||
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Annotation | Cryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. Half map 1. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Cryo-EM structure of long form insulin receptor (IR-B)...
File | emd_41878_half_map_2.map | ||||||||||||
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Annotation | Cryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. Half map 2. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Long form insulin receptor (IR-B) with four IGF2 bound, symmetric...
Entire | Name: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. |
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Components |
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-Supramolecule #1: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric...
Supramolecule | Name: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Insulin receptor
Macromolecule | Name: Insulin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 156.518328 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE ...String: MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE DNYIVLNKDD NEECGDICPG TAKGKTNCPA TVINGQFVER CWTHSHCQKV CPTICKSHGC TAEGLCCHSE CL GNCSQPD DPTKCVACRN FYLDGRCVET CPPPYYHFQD WRCVNFSFCQ DLHHKCKNSR RQGCHQYVIH NNKCIPECPS GYT MNSSNL LCTPCLGPCP KVCHLLEGEK TIDSVTSAQE LRGCTVINGS LIINIRGGNN LAAELEANLG LIEEISGYLK IRRS YALVS LSFFRKLRLI RGETLEIGNY SFYALDNQNL RQLWDWSKHN LTITQGKLFF HYNPKLCLSE IHKMEEVSGT KGRQE RNDI ALKTNGDQAS CENELLKFSY IRTSFDKILL RWEPYWPPDF RDLLGFMLFY KEAPYQNVTE FDGQDACGSN SWTVVD IDP PLRSNDPKSQ NHPGWLMRGL KPWTQYAIFV KTLVTFSDER RTYGAKSDII YVQTDATNPS VPLDPISVSN SSSQIIL KW KPPSDPNGNI THYLVFWERQ AEDSELFELD YCLKGLKLPS RTWSPPFESE DSQKHNQSEY EDSAGECCSC PKTDSQIL K ELEESSFRKT FEDYLHNVVF VPRKTSSGTG AEDPRPSRKR RSLGDVGNVT VAVPTVAAFP NTSSTSVPTS PEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYR RYGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRIRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII G PLIFVFLF SVVIGSIYLF LRKRQPDGPL GPLYASSNPE YLSASDVFPC SVYVPDEWEV SREKITLLRE LGQGSFGMVY EG NARDIIK GEAETRVAVK TVNESASLRE RIEFLNEASV MKGFTCHHVV RLLGVVSKGQ PTLVVMELMA HGDLKSYLRS LRP EAENNP GRPPPTLQEM IQMAAEIADG MAYLNAKKFV HRDLAARNCM VAHDFTVKIG DFGMTRDIYE TDYYRKGGKG LLPV RWMAP ESLKDGVFTT SSDMWSFGVV LWEITSLAEQ PYQGLSNEQV LKFVMDGGYL DQPDNCPERV TDLMRMCWQF NPKMR PTFL EIVNLLKDDL HPSFPEVSFF HSEENKAPES EELEMEFEDM ENVPLDRSSH CQREEAGGRD GGSSLGFKRS YEEHIP YTH MNGGKKNGRI LTLPRSNPS UniProtKB: Insulin receptor |
-Macromolecule #2: Insulin-like growth factor II
Macromolecule | Name: Insulin-like growth factor II / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 20.170398 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MGIPMGKSML VLLTFLAFAS CCIAAYRPSE TLCGGELVDT LQFVCGDRGF YFSRPASRVS RRSRGIVEEC CFRSCDLALL ETYCATPAK SERDVSTPPT VLPDNFPRYP VGKFFQYDTW KQSTQRLRRG LPALLRARRG HVLAKELEAF REAKRHRPLI A LPTQDPAH GGAPPEMASN RK UniProtKB: Insulin-like growth factor II |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.6 µm |
Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Particle selection | Number selected: 3962294 |
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Startup model | Type of model: OTHER |
Initial angle assignment | Type: PROJECTION MATCHING / Software - Name: RELION |
Final 3D classification | Software - Name: RELION |
Final angle assignment | Type: PROJECTION MATCHING / Software - Name: RELION |
Final reconstruction | Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 74973 |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: RIGID BODY FIT |
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Output model | PDB-8u4c: |