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Yorodumi- EMDB-23951: The insulin receptor ectodomain in complex with three venom hybri... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23951 | |||||||||
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Title | The insulin receptor ectodomain in complex with three venom hybrid insulin molecules - asymmetric conformation | |||||||||
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Sample |
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Function / homology | Function and homology information negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / regulation of cellular amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of reactive oxygen species biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / acute-phase response / Regulation of insulin secretion / negative regulation of protein catabolic process / endosome lumen / positive regulation of glucose import / positive regulation of protein secretion / receptor protein-tyrosine kinase / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin receptor binding / wound healing / regulation of synaptic plasticity / vasodilation / hormone activity / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / glucose metabolic process / regulation of protein localization / glucose homeostasis / insulin receptor signaling pathway / cell-cell signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of NF-kappaB transcription factor activity / positive regulation of cell growth / protease binding / secretory granule lumen / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / Golgi membrane / endoplasmic reticulum lumen / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.4 Å | |||||||||
Authors | Blakely AD / Xiong X / Kim JH / Menting J / Schafer IB / Schubert HL / Agrawal R / Gutmann T / Delaine C / Zhang Y ...Blakely AD / Xiong X / Kim JH / Menting J / Schafer IB / Schubert HL / Agrawal R / Gutmann T / Delaine C / Zhang Y / Artik GO / Merriman A / Eckert D / Lawrence MC / Coskun U / Fisher SJ / Forbes BE / Safavi-Hemami H / Hill CP / Chou DHC | |||||||||
Funding support | 1 items
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Citation | Journal: Nat Chem Biol / Year: 2022 Title: Symmetric and asymmetric receptor conformation continuum induced by a new insulin. Authors: Xiaochun Xiong / Alan Blakely / Jin Hwan Kim / John G Menting / Ingmar B Schäfer / Heidi L Schubert / Rahul Agrawal / Theresia Gutmann / Carlie Delaine / Yi Wolf Zhang / Gizem Olay Artik / ...Authors: Xiaochun Xiong / Alan Blakely / Jin Hwan Kim / John G Menting / Ingmar B Schäfer / Heidi L Schubert / Rahul Agrawal / Theresia Gutmann / Carlie Delaine / Yi Wolf Zhang / Gizem Olay Artik / Allanah Merriman / Debbie Eckert / Michael C Lawrence / Ünal Coskun / Simon J Fisher / Briony E Forbes / Helena Safavi-Hemami / Christopher P Hill / Danny Hung-Chieh Chou / Abstract: Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active ...Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions. | |||||||||
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_23951.map.gz | 59.4 MB | EMDB map data format | |
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Header (meta data) | emd-23951-v30.xml emd-23951.xml | 19.1 KB 19.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23951_fsc.xml | 8.9 KB | Display | FSC data file |
Images | emd_23951.png | 23.3 KB | ||
Masks | emd_23951_msk_1.map | 64 MB | Mask map | |
Others | emd_23951_half_map_1.map.gz emd_23951_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23951 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23951 | HTTPS FTP |
-Related structure data
Related structure data | 7mqsMC 7mqoC 7mqrC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10736 (Title: Cryo-EM of the human insulin receptor ectodomain in complex with an insulin analog with truncated B chain and enlongated A chain Data size: 11.7 TB Data #1: Unaligned multi-frame micrographs (40 e-/A2 dose) [micrographs - multiframe] Data #2: unaligned micrographs (60 e-/A2 dose) [micrographs - multiframe]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23951.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.365 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_23951_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_23951_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_23951_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Insulin receptor ectodomain in complex with insulin analog Vh-Ins...
Entire | Name: Insulin receptor ectodomain in complex with insulin analog Vh-Ins-HSLQ - asymmetric conformation. |
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Components |
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-Supramolecule #1: Insulin receptor ectodomain in complex with insulin analog Vh-Ins...
Supramolecule | Name: Insulin receptor ectodomain in complex with insulin analog Vh-Ins-HSLQ - asymmetric conformation. type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 209 KDa |
-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: 104.632695 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
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 DVPSNIA |
-Macromolecule #2: Insulin A chain
Macromolecule | Name: Insulin A chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 2.736106 KDa |
Sequence | String: GIVEQCCTSI CSLYQLENYC HSLQ |
-Macromolecule #3: Insulin B chain
Macromolecule | Name: Insulin B chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 2.537951 KDa |
Sequence | String: FVNQHLCGSE LVEALYLVCL ER |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 / Component: (Name: HEPES, Tris) Details: Equal parts HBS(50 mM HEPES pH 7.5, 150 mM NaCl ) and TBS (25 mM Tris pH 8.5, 150 mM NaCl) |
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Grid | Model: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK II |
-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: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |