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- EMDB-27704: Cryo-EM structure of insulin receptor (IR) bound with S597 peptide -

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Basic information

Entry
Database: EMDB / ID: EMD-27704
TitleCryo-EM structure of insulin receptor (IR) bound with S597 peptide
Map dataCryo-EM map of insulin receptor (IR) bound with S597 peptide
Sample
  • Complex: Insulin receptor bound with S597 peptide
    • Protein or peptide: Insulin mimetic peptide S597
    • Protein or peptide: Insulin receptor
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 / adrenal gland development / neuronal cell body membrane / negative regulation of feeding behavior / amyloid-beta clearance / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / insulin receptor substrate binding / epidermis development / positive regulation of glycogen biosynthetic process / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of phosphorylation / dendrite membrane / insulin-like growth factor receptor binding / neuron projection maintenance / positive regulation of glycolytic process / response to nutrient levels / receptor-mediated endocytosis / positive regulation of mitotic nuclear division / negative regulation of protein phosphorylation / caveola / positive regulation of glucose import / animal organ morphogenesis / receptor internalization / receptor protein-tyrosine kinase / cellular response to growth factor stimulus / cellular response to insulin stimulus / recycling endosome membrane / male gonad development / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of nitric oxide biosynthetic process / late endosome / glucose homeostasis / insulin receptor signaling pathway / nuclear envelope / amyloid-beta binding / protein phosphatase binding / protein tyrosine kinase activity / positive regulation of MAPK cascade / protein autophosphorylation / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome / protein kinase activity / positive regulation of cell migration / positive regulation of protein phosphorylation / symbiont entry into host cell / G protein-coupled receptor signaling pathway / axon / protein domain specific binding / external side of plasma membrane / negative regulation of gene expression / neuronal cell body / positive regulation of cell population proliferation / protein-containing complex binding / regulation of DNA-templated transcription / GTP binding / protein kinase binding / structural molecule activity / positive regulation of DNA-templated transcription / ATP binding / membrane / identical protein binding / plasma membrane
Similarity search - Function
Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.4 Å
AuthorsPark J / Li J / Mayer JP / Ball KA / Wu JY / Hall C / Accili D / Stowell MHB / Bai XC / Choi E
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM136976 United States
CitationJournal: Nat Commun / Year: 2022
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
DepositionJul 25, 2022-
Header (metadata) releaseSep 7, 2022-
Map releaseSep 7, 2022-
UpdateOct 12, 2022-
Current statusOct 12, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27704.png

Downloads & links

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Map

FileDownload / File: emd_27704.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of insulin receptor (IR) bound with S597 peptide
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.006
Minimum - Maximum-0.0047827708 - 0.018255085
Average (Standard dev.)0.000119500786 (±0.0010405079)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Insulin receptor bound with S597 peptide

EntireName: Insulin receptor bound with S597 peptide
Components
  • Complex: Insulin receptor bound with S597 peptide
    • Protein or peptide: Insulin mimetic peptide S597
    • Protein or peptide: Insulin receptor

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Supramolecule #1: Insulin receptor bound with S597 peptide

SupramoleculeName: Insulin receptor bound with S597 peptide / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Insulin mimetic peptide S597

MacromoleculeName: Insulin mimetic peptide S597 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 3.789079 KDa
SequenceString:
SLEEEWAQIE CEVYGRGCPS ESFYDWFERQ L

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Macromolecule #2: Insulin receptor

MacromoleculeName: Insulin receptor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 153.232578 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration6 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.6 µm
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm 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

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Image processing

Particle selectionNumber selected: 1282550
CTF correctionSoftware - Name: Gctf
Startup modelType of model: OTHER / Details: From RELION
Initial angle assignmentType: PROJECTION MATCHING
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 5.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 152565

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-8dtl:
Cryo-EM structure of insulin receptor (IR) bound with S597 peptide

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