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Yorodumi- EMDB-25190: Full-length insulin receptor bound with site 2 binding deficient ... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-25190 | |||||||||
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Title | Full-length insulin receptor bound with site 2 binding deficient mutant insulin (A-L13R) -- symmetric conformation | |||||||||
Map data | Cryo-EM structure of full-length insulin receptor bound with site 2 binding deficient mutant insulin (A-L13R) -- symmetric conformation | |||||||||
Sample |
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Function / homology | Function and homology information Signaling by Insulin receptor / Insulin receptor recycling / yolk / IRS activation / Insulin receptor signalling cascade / Signal attenuation / 3-phosphoinositide-dependent protein kinase binding / positive regulation of glycoprotein biosynthetic process / lipoic acid binding / regulation of hydrogen peroxide metabolic process ...Signaling by Insulin receptor / Insulin receptor recycling / yolk / IRS activation / Insulin receptor signalling cascade / Signal attenuation / 3-phosphoinositide-dependent protein kinase binding / positive regulation of glycoprotein biosynthetic process / lipoic acid binding / regulation of hydrogen peroxide metabolic process / regulation of female gonad development / positive regulation of meiotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 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 / insulin receptor activity / nuclear lumen / positive regulation of protein-containing complex disassembly / cargo receptor activity / dendritic spine maintenance / insulin binding / PTB domain binding / negative regulation of NAD(P)H oxidase activity / neuronal cell body membrane / adrenal gland development / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / negative regulation of fatty acid metabolic process / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / amyloid-beta clearance / positive regulation of peptide hormone secretion / Regulation of gene expression in beta cells / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / positive regulation of dendritic spine maintenance / alpha-beta T cell activation / negative regulation of acute inflammatory response / negative regulation of respiratory burst involved in inflammatory response / insulin receptor substrate binding / negative regulation of protein secretion / fatty acid homeostasis / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / positive regulation of glycogen biosynthetic process / positive regulation of lipid biosynthetic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / response to tumor necrosis factor / positive regulation of nitric oxide mediated signal transduction / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / phosphatidylinositol 3-kinase binding / negative regulation of lipid catabolic process / heart morphogenesis / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / positive regulation of phosphorylation / transport vesicle / positive regulation of protein autophosphorylation / dendrite membrane / Insulin receptor recycling / insulin-like growth factor receptor binding / receptor-mediated endocytosis / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / response to nutrient levels / positive regulation of mitotic nuclear division / negative regulation of protein phosphorylation / Regulation of insulin secretion / positive regulation of nitric-oxide synthase activity / positive regulation of long-term synaptic potentiation / caveola / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of protein secretion / regulation of transmembrane transporter activity / positive regulation of cell differentiation / positive regulation of glucose import / negative regulation of proteolysis / animal organ morphogenesis / regulation of synaptic plasticity Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) / Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Bai XC / Choi E | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Nat Struct Mol Biol / Year: 2022 Title: Synergistic activation of the insulin receptor via two distinct sites. Authors: Jie Li / Junhee Park / John P Mayer / Kristofor J Webb / Emiko Uchikawa / Jiayi Wu / Shun Liu / Xuewu Zhang / Michael H B Stowell / Eunhee Choi / Xiao-Chen Bai / Abstract: Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional ...Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_25190.map.gz | 96.1 MB | EMDB map data format | |
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Header (meta data) | emd-25190-v30.xml emd-25190.xml | 14.8 KB 14.8 KB | Display Display | EMDB header |
Images | emd_25190.png | 33.9 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25190 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25190 | HTTPS FTP |
-Related structure data
Related structure data | 7sl3MC 7sl1C 7sl2C 7sl4C 7sl6C 7sl7C 7sthC 7stiC 7stjC 7stkC C: citing same article (ref.) M: atomic model generated by this map |
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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_25190.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Cryo-EM structure of full-length insulin receptor bound with site 2 binding deficient mutant insulin (A-L13R) -- 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
-Sample components
-Entire : Full-length insulin receptor bound with site 2 binding deficient ...
Entire | Name: Full-length insulin receptor bound with site 2 binding deficient mutant insulin (A-L13R) -- symmetric conformation |
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Components |
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-Supramolecule #1: Full-length insulin receptor bound with site 2 binding deficient ...
Supramolecule | Name: Full-length insulin receptor bound with site 2 binding deficient mutant insulin (A-L13R) -- symmetric conformation type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all |
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-Macromolecule #1: Insulin receptor
Macromolecule | Name: Insulin 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: 155.790516 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE ...String: MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE DNYIVLNKDD NEECGDVCPG TAKGKTNCPA TVINGQFVER CWTHSHCQKV CPTICKSHGC TAEGLCCHKE CL GNCSEPD DPTKCVACRN FYLDGQCVET CPPPYYHFQD WRCVNFSFCQ DLHFKCRNSR KPGCHQYVIH NNKCIPECPS GYT MNSSNL MCTPCLGPCP KVCQILEGEK TIDSVTSAQE LRGCTVINGS LIINIRGGNN LAAELEANLG LIEEISGFLK IRRS YALVS LSFFRKLHLI RGETLEIGNY SFYALDNQNL RQLWDWSKHN LTITQGKLFF HYNPKLCLSE IHKMEEVSGT KGRQE RNDI ALKTNGDQAS CENELLKFSF IRTSFDKILL RWEPYWPPDF RDLLGFMLFY KEAPYQNVTE FDGQDACGSN SWTVVD IDP PQRSNDPKSQ TPSHPGWLMR GLKPWTQYAI FVKTLVTFSD ERRTYGAKSD IIYVQTDATN PSVPLDPISV SNSSSQI IL KWKPPSDPNG NITHYLVYWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SDDSQKHNQS EYDDSASECC SCPKTDSQ I LKELEESSFR KTFEDYLHNV VFVPRPSRKR RSLEEVGNVT ATTLTLPDFP NVSSTIVPTS QEEHRPFEKV VNKESLVIS GLRHFTGYRI ELQACNQDSP DERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRVRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII GPLIFVFLFS V VIGSIYLF LRKRQPDGPM GPLYASSNPE YLSASDVFPS SVYVPDEWEV PREKITLLRE LGQGSFGMVY EGNAKDIIKG EA ETRVAVK TVNESASLRE RIEFLNEASV MKGFTCHHVV RLLGVVSKGQ PTLVVMELMA HGDLKSHLRS LRPDAENNPG RPP PTLQEM IQMTAEIADG MAYLNAKKFV HRDLAARNCM VAHDFTVKIG DFGMTRDIYE TDYYRKGGKG LLPVRWMSPE SLKD GVFTA SSDMWSFGVV LWEITSLAEQ PYQGLSNEQV LKFVMDGGYL DPPDNCPERL TDLMRMCWQF NPKMRPTFLE IVNLL KDDL HPSFPEVSFF YSEENKAPES EELEMEFEDM ENVPLDRSSH CQREEAGGRE GGSSLSIKRT YDEHIPYTHM NGGKKN GRV LTLPRSNPS |
-Macromolecule #2: Insulin B chain
Macromolecule | Name: Insulin B chain / 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: 3.433953 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: FVNQHLCGSH LVEALYLVCG ERGFFYTPKT |
-Macromolecule #3: Insulin A chain
Macromolecule | Name: Insulin A chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 2.427734 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: GIVEQCCTSI CSRYQLENYC N |
-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: 8 |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV |
-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 |
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: 1118695 |
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CTF correction | Software - Name: Gctf |
Startup model | Type of model: OTHER / Details: From RELION3 |
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: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 104877 |