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- EMDB-27704: Cryo-EM structure of insulin receptor (IR) bound with S597 peptide -
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Open data
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Basic information
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Title | Cryo-EM structure of insulin receptor (IR) bound with S597 peptide | |||||||||
![]() | Cryo-EM map of insulin receptor (IR) bound with S597 peptide | |||||||||
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Function / homology | ![]() Signaling by Insulin receptor / yolk / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / 3-phosphoinositide-dependent protein kinase binding / positive regulation of glycoprotein biosynthetic process / lipoic acid binding / regulation of female gonad development ...Signaling by Insulin receptor / yolk / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / 3-phosphoinositide-dependent protein kinase binding / positive regulation of glycoprotein biosynthetic process / lipoic acid binding / regulation of female gonad development / regulation of hydrogen peroxide metabolic process / positive regulation of meiotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / nuclear lumen / insulin-like growth factor II binding / positive regulation of developmental growth / 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 / PTB domain binding / adrenal gland development / negative regulation of feeding behavior / neuronal cell body membrane / amyloid-beta clearance / positive regulation of respiratory burst / positive regulation of phosphorylation / positive regulation of receptor internalization / regulation of embryonic development / insulin receptor substrate binding / positive regulation of glycogen biosynthetic process / epidermis development / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / heart morphogenesis / dendrite membrane / insulin-like growth factor receptor binding / neuron projection maintenance / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / response to nutrient levels / receptor-mediated endocytosis / negative regulation of protein phosphorylation / caveola / positive regulation of glucose import / receptor protein-tyrosine kinase / animal organ morphogenesis / receptor internalization / cellular response to growth factor stimulus / recycling endosome membrane / nuclear envelope / male gonad development / positive regulation of nitric oxide biosynthetic process / glucose homeostasis / late endosome / insulin receptor signaling pathway / amyloid-beta binding / protein phosphatase binding / protein tyrosine kinase activity / protein autophosphorylation / receptor complex / positive regulation of MAPK cascade / endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / lysosome / positive regulation of cell migration / protein kinase activity / positive regulation of protein phosphorylation / symbiont entry into host cell / protein domain specific binding / G protein-coupled receptor signaling pathway / external side of plasma membrane / axon / negative regulation of gene expression / neuronal cell body / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / protein-containing complex binding / GTP binding / protein kinase binding / ATP binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 5.4 Å | |||||||||
![]() | Park J / Li J / Mayer JP / Ball KA / Wu JY / Hall C / Accili D / Stowell MHB / Bai XC / Choi E | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Activation of the insulin receptor by an insulin mimetic peptide. Authors: Junhee Park / Jie Li / John P Mayer / Kerri A Ball / Jiayi Wu / Catherine Hall / Domenico Accili / Michael H B Stowell / Xiao-Chen Bai / Eunhee Choi / ![]() Abstract: Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity ...Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin's action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 164.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14 KB 14 KB | Display Display | ![]() |
Images | ![]() | 21.8 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 429.5 KB | Display | ![]() |
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Full document | ![]() | 429.1 KB | Display | |
Data in XML | ![]() | 6.6 KB | Display | |
Data in CIF | ![]() | 7.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8dtlMC ![]() 8dtmC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Cryo-EM map of insulin receptor (IR) bound with S597 peptide | ||||||||||||||||||||
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
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Sample components
-Entire : Insulin receptor bound with S597 peptide
Entire | Name: Insulin receptor bound with S597 peptide |
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Components |
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-Supramolecule #1: Insulin receptor bound with S597 peptide
Supramolecule | Name: Insulin receptor bound with S597 peptide / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Insulin mimetic peptide S597
Macromolecule | Name: Insulin mimetic peptide S597 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 3.789079 KDa |
Sequence | String: SLEEEWAQIE CEVYGRGCPS ESFYDWFERQ L |
-Macromolecule #2: Insulin receptor
Macromolecule | Name: Insulin receptor / 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: ![]() ![]() |
Molecular weight | Theoretical: 153.232578 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDVC P GTAKGKTN ...String: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDVC P GTAKGKTN CPATVINGQF VERCWTHSHC QKVCPTICKS HGCTAEGLCC HKECLGNCSE PDDPTKCVAC RNFYLDGQCV ET CPPPYYH FQDWRCVNFS FCQDLHFKCR NSRKPGCHQY VIHNNKCIPE CPSGYTMNSS NLMCTPCLGP CPKVCQILEG EKT IDSVTS AQELRGCTVI NGSLIINIRG GNNLAAELEA NLGLIEEISG FLKIRRSYAL VSLSFFRKLH LIRGETLEIG NYSF YALDN QNLRQLWDWS KHNLTITQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDQ ASCENELLKF SFIRT SFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN VTEFDGQDAC GSNSWTVVDI DPPQRSNDPK SQTPSHPGWL MRGLKP WTQ YAIFVKTLVT FSDERRTYGA KSDIIYVQTD ATNPSVPLDP ISVSNSSSQI ILKWKPPSDP NGNITHYLVY WERQAED SE LFELDYCLKG LKLPSRTWSP PFESDDSQKH NQSEYDDSAS ECCSCPKTDS QILKELEESS FRKTFEDYLH NVVFVPRP S RKRRSLEEVG NVTATTLTLP DFPNVSSTIV PTSQEEHRPF EKVVNKESLV ISGLRHFTGY RIELQACNQD SPDERCSVA AYVSARTMPE AKADDIVGPV THEIFENNVV HLMWQEPKEP NGLIVLYEVS YRRYGDEELH LCVSRKHFAL ERGCRLRGLS PGNYSVRVR ATSLAGNGSW TEPTYFYVTD YLDVPSNIAK IIIGPLIFVF LFSVVIGSIY LFLRKRQPDG PMGPLYASSN P EYLSASDV FPSSVYVPDE WEVPREKITL LRELGQGSFG MVYEGNAKDI IKGEAETRVA VKTVNESASL RERIEFLNEA SV MKGFTCH HVVRLLGVVS KGQPTLVVME LMAHGDLKSH LRSLRPDAEN NPGRPPPTLQ EMIQMTAEIA DGMAYLNAKK FVH RDLAAR NCMVAHDFTV KIGDFGMTRD IYETDYYRKG GKGLLPVRWM SPESLKDGVF TASSDMWSFG VVLWEITSLA EQPY QGLSN EQVLKFVMDG GYLDPPDNCP ERLTDLMRMC WQFNPKMRPT FLEIVNLLKD DLHPSFPEVS FFYSEENKAP ESEEL EMEF EDMENVPLDR SSHCQREEAG GREGGSSLSI KRTYDEHIPY THMNGGKKNG RVLTLPRSNP S |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 6 mg/mL |
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Buffer | pH: 7.4 |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE |
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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: ![]() |
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 |
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Image processing
-Atomic model buiding 1
Refinement | Protocol: RIGID BODY FIT |
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Output model | ![]() PDB-8dtl: |