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- EMDB-27705: Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 -

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Basic information

Entry
Database: EMDB / ID: EMD-27705
TitleCryo-EM structure of insulin receptor (IR) bound with S597 component 2
Map dataCryo-EM structure of insulin receptor (IR) bound with S597 component 2
Sample
  • Complex: Insulin receptor bound with S597 component 2
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin mimetic peptide S597 component 2
Function / homology
Function and homology information


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 / 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 / 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 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 / positive regulation of phosphorylation / dendrite membrane / 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 / animal organ morphogenesis / insulin-like growth factor receptor binding / receptor internalization / receptor protein-tyrosine kinase / cellular response to growth factor stimulus / recycling endosome membrane / male gonad development / positive regulation of nitric oxide biosynthetic process / late endosome / insulin receptor signaling pathway / glucose homeostasis / nuclear envelope / amyloid-beta binding / protein phosphatase binding / protein tyrosine kinase activity / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / lysosome / receptor complex / protein kinase activity / endosome / positive regulation of cell migration / symbiont entry into host cell / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / protein domain specific binding / external side of plasma membrane / axon / negative regulation of gene expression / neuronal cell body / positive regulation of cell population proliferation / protein-containing complex binding / GTP binding / protein kinase binding / positive regulation of DNA-templated transcription / ATP binding / membrane / 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: 3.5 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 26, 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_27705.png

Downloads & links

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Map

FileDownload / File: emd_27705.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of insulin receptor (IR) bound with S597 component 2
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.104250565 - 0.17525329
Average (Standard dev.)6.743511e-05 (±0.0026620703)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 324.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of insulin receptor (IR) bound with...

Fileemd_27705_half_map_1.map
AnnotationCryo-EM structure of insulin receptor (IR) bound with S597 component 2 -- half map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of insulin receptor (IR) bound with...

Fileemd_27705_half_map_2.map
AnnotationCryo-EM structure of insulin receptor (IR) bound with S597 component 2 -- half map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Insulin receptor bound with S597 component 2

EntireName: Insulin receptor bound with S597 component 2
Components
  • Complex: Insulin receptor bound with S597 component 2
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin mimetic peptide S597 component 2

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Supramolecule #1: Insulin receptor bound with S597 component 2

SupramoleculeName: Insulin receptor bound with S597 component 2 / 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 receptor

MacromoleculeName: Insulin receptor / type: protein_or_peptide / ID: 1 / 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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Macromolecule #2: Insulin mimetic peptide S597 component 2

MacromoleculeName: Insulin mimetic peptide S597 component 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 2.286474 KDa
SequenceString:
SLEEEWAQIE CEVYGRGCPS

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination 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

Particle selectionNumber selected: 2789169
CTF correctionSoftware - Name: Gctf
Startup modelType of model: OTHER / Details: From RELION
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 135709
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-8dtm:
Cryo-EM structure of insulin receptor (IR) bound with S597 component 2

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