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Yorodumi- EMDB-23767: Insulin receptor ectodomain dimer complexed with two IRPA-9 parti... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23767 | |||||||||
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Title | Insulin receptor ectodomain dimer complexed with two IRPA-9 partial agonists | |||||||||
Map data | Main map used for the reconstruction. | |||||||||
Sample |
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Function / homology | Function and homology information regulation of female gonad development / positive regulation of meiotic cell cycle / 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 / positive regulation of protein-containing complex disassembly ...regulation of female gonad development / positive regulation of meiotic cell cycle / 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 / positive regulation of protein-containing complex disassembly / cargo receptor activity / dendritic spine maintenance / insulin binding / negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / PTB domain binding / adrenal gland development / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / activation of protein kinase activity / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / neuronal cell body membrane / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of receptor internalization / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / amyloid-beta clearance / alpha-beta T cell activation / transport across blood-brain barrier / regulation of amino acid metabolic process / regulation of embryonic development / negative regulation of respiratory burst involved in inflammatory response / insulin receptor substrate binding / negative regulation of protein secretion / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / epidermis development / Synthesis, secretion, and deacylation of Ghrelin / regulation of protein localization to plasma membrane / fatty acid homeostasis / negative regulation of gluconeogenesis / negative regulation of lipid catabolic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of lipid biosynthetic process / positive regulation of insulin receptor signaling pathway / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / nitric oxide-cGMP-mediated signaling / positive regulation of protein autophosphorylation / insulin-like growth factor receptor binding / transport vesicle / Insulin receptor recycling / dendrite membrane / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / positive regulation of nitric-oxide synthase activity / learning / acute-phase response / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / cognition / Regulation of insulin secretion / endosome lumen / positive regulation of D-glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin receptor binding / positive regulation of MAP kinase activity / wound healing / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / caveola / regulation of synaptic plasticity / hormone activity / cellular response to growth factor stimulus / receptor internalization / memory / positive regulation of neuron projection development / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / positive regulation of protein localization to nucleus Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 5.2 Å | |||||||||
Authors | Gomez-Llorente Y / Zhou H / Scapin G | |||||||||
Citation | Journal: Nat Commun / Year: 2022 Title: Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists. Authors: Margaret Wu / Ester Carballo-Jane / Haihong Zhou / Peter Zafian / Ge Dai / Mindy Liu / Julie Lao / Terri Kelly / Dan Shao / Judith Gorski / Dmitri Pissarnitski / Ahmet Kekec / Ying Chen / ...Authors: Margaret Wu / Ester Carballo-Jane / Haihong Zhou / Peter Zafian / Ge Dai / Mindy Liu / Julie Lao / Terri Kelly / Dan Shao / Judith Gorski / Dmitri Pissarnitski / Ahmet Kekec / Ying Chen / Stephen F Previs / Giovanna Scapin / Yacob Gomez-Llorente / Scott A Hollingsworth / Lin Yan / Danqing Feng / Pei Huo / Geoffrey Walford / Mark D Erion / David E Kelley / Songnian Lin / James Mu / Abstract: Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, ...Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23767.map.gz | 85.3 MB | EMDB map data format | |
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Header (meta data) | emd-23767-v30.xml emd-23767.xml | 20.8 KB 20.8 KB | Display Display | EMDB header |
Images | emd_23767.png | 131.3 KB | ||
Masks | emd_23767_msk_1.map | 91.1 MB | Mask map | |
Others | emd_23767_half_map_1.map.gz emd_23767_half_map_2.map.gz | 84.4 MB 84.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23767 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23767 | HTTPS FTP |
-Validation report
Summary document | emd_23767_validation.pdf.gz | 888.1 KB | Display | EMDB validaton report |
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Full document | emd_23767_full_validation.pdf.gz | 887.7 KB | Display | |
Data in XML | emd_23767_validation.xml.gz | 12.8 KB | Display | |
Data in CIF | emd_23767_validation.cif.gz | 14.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23767 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23767 | HTTPS FTP |
-Related structure data
Related structure data | 7md5MC 7md4C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23767.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Main map used for the reconstruction. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_23767_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Half map A.
File | emd_23767_half_map_1.map | ||||||||||||
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Annotation | Half map A. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map B.
File | emd_23767_half_map_2.map | ||||||||||||
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Annotation | Half map B. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : IR-ECD dimer complexed with two IRPA-9 full agonists
Entire | Name: IR-ECD dimer complexed with two IRPA-9 full agonists |
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Components |
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-Supramolecule #1: IR-ECD dimer complexed with two IRPA-9 full agonists
Supramolecule | Name: IR-ECD dimer complexed with two IRPA-9 full agonists / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Molecular weight | Experimental: 230 KDa |
-Supramolecule #2: IR-ECD dimer
Supramolecule | Name: IR-ECD dimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Mus musculus (house mouse) |
-Supramolecule #3: IRPA-9 full agonist
Supramolecule | Name: IRPA-9 full agonist / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Escherichia coli (E. coli) |
-Macromolecule #1: Isoform Short of Insulin receptor
Macromolecule | Name: Isoform Short of 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: Homo sapiens (human) |
Molecular weight | Theoretical: 106.143359 KDa |
Recombinant expression | Organism: Mus musculus (house mouse) |
Sequence | String: 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 VFVPRPSR K RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAY VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRIRAT SLAGNGSWTE PTYFYVTDYL DVPSNIAKHH HHHHHHHH |
-Macromolecule #2: Isoform Short of Insulin receptor alpha
Macromolecule | Name: Isoform Short of Insulin receptor alpha / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 3.459836 KDa |
Recombinant expression | Organism: Mus musculus (house mouse) |
Sequence | String: AAAKELEESS FRKTFEDYLH NVVFVPSPSR |
-Macromolecule #3: Insulin chain A
Macromolecule | Name: Insulin chain A / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 2.383698 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: GIVEQCCTSI CSLYQLENYC N |
-Macromolecule #4: Insulin B chain
Macromolecule | Name: Insulin B chain / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 3.433953 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: FVNQHLCGSH LVEALYLVCG ERGFFYTPKT |
-Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 4 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Grid | Model: Homemade / Material: COPPER / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: PLASMA CLEANING |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 45.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: INSILICO MODEL / In silico model: ab-initio from cryoSPARC. |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 5.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 54293 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |