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- EMDB-10273: human insulin receptor ectodomain bound by 4 insulin -

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Basic information

Entry
Database: EMDB / ID: EMD-10273
Titlehuman insulin receptor ectodomain bound by 4 insulin
Map data"manually filtered map" in paper, b-factor=-140
Sample
  • Complex: human insulin receptor ectodomain bound to four insulin
    • Complex: human insulin receptor ectodomain bound to four insulin
      • Protein or peptide: Insulin receptor
      • Protein or peptide: Insulin receptor
    • Complex: human insulin receptor ectodomain bound to four insulin
      • Protein or peptide: Insulin
      • Protein or peptide: Insulin
Keywordscell surface receptor / insulin / tyrosine kinase receptor / glucose homeostasis / hormone / diabetes / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / dendritic spine maintenance ...regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / dendritic spine maintenance / insulin binding / : / cargo receptor activity / negative regulation of glycogen catabolic process / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / PTB domain binding / IRS activation / Insulin processing / regulation of protein secretion / negative regulation of feeding behavior / positive regulation of peptide hormone secretion / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / positive regulation of respiratory burst / neuronal cell body membrane / alpha-beta T cell activation / amyloid-beta clearance / heart morphogenesis / positive regulation of receptor internalization / insulin receptor substrate binding / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of gluconeogenesis / negative regulation of protein secretion / positive regulation of dendritic spine maintenance / fatty acid homeostasis / positive regulation of brown fat cell differentiation / positive regulation of glycogen biosynthetic process / positive regulation of insulin receptor signaling pathway / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of lipid biosynthetic process / negative regulation of respiratory burst involved in inflammatory response / protein kinase activator activity / negative regulation of lipid catabolic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / nitric oxide-cGMP-mediated signaling / regulation of protein localization to plasma membrane / transport vesicle / phosphatidylinositol 3-kinase binding / transport across blood-brain barrier / Insulin receptor recycling / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / positive regulation of D-glucose import across plasma membrane / positive regulation of mitotic nuclear division / neuron projection maintenance / male gonad development / endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis / positive regulation of glycolytic process / learning / Insulin receptor signalling cascade / regulation of embryonic development / dendrite membrane / endosome lumen / positive regulation of protein secretion / acute-phase response / positive regulation of cytokine production / wound healing / insulin receptor binding / positive regulation of long-term synaptic potentiation / positive regulation of neuron projection development / glucose metabolic process / positive regulation of cell differentiation / negative regulation of protein catabolic process / Regulation of insulin secretion / memory / regulation of synaptic plasticity / receptor protein-tyrosine kinase / hormone activity / positive regulation of protein localization to nucleus / vasodilation / caveola / Golgi lumen / cognition / insulin receptor signaling pathway / positive regulation of nitric oxide biosynthetic process / glucose homeostasis / cellular response to insulin stimulus / late endosome / regulation of protein localization / cell-cell signaling / protein autophosphorylation / positive regulation of cell growth / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
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. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. ...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. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily / 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 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
Insulin / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsGutmann T / Schaefer IB
Funding support Germany, Finland, 4 items
OrganizationGrant numberCountry
German Research Foundation251981924TRR83 Germany
German Research Foundation347368302 FOR2682 Germany
European Research CouncilCROWDED-PRO-LIPIDS Finland
Academy of Finland Finland
Citation
Journal: J Cell Biol / Year: 2020
Title: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain.
Authors: Theresia Gutmann / Ingmar B Schäfer / Chetan Poojari / Beate Brankatschk / Ilpo Vattulainen / Mike Strauss / Ünal Coskun /
Abstract: Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current ...Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.
#1: Journal: bioRxiv / Year: 2019
Title: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain
Authors: Gutmann T / Schafer IB / Poojari C / Brankatschk B / Vattulainen I / Strauss M / Coskun U
History
DepositionAug 29, 2019-
Header (metadata) releaseNov 13, 2019-
Map releaseNov 13, 2019-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 17
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 17
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6sof
  • Surface level: 17
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_10273.png

Downloads & links

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Map

FileDownload / File: emd_10273.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation"manually filtered map" in paper, b-factor=-140
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 288 pix.
= 305.28 Å		1.06 Å/pix.
x 288 pix.
= 305.28 Å		1.06 Å/pix.
x 288 pix.
= 305.28 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015 / Movie #1: 17
Minimum - Maximum-27.025113999999999 - 55.418995000000002
Average (Standard dev.)0.15409243 (±1.8208048)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 305.27997 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z305.280305.280305.280
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ280280280
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-27.02555.4190.154

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Supplemental data

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Mask #1

Fileemd_10273_msk_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Additional map: "automatically filtered map" in paper, b-factor=-172

Fileemd_10273_additional.map
Annotation"automatically filtered map" in paper, b-factor=-172
Projections & Slices
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Half map: half-map 1 post Bayesian polishing

Fileemd_10273_half_map_1.map
Annotationhalf-map 1 post Bayesian polishing
Projections & Slices
AxesZYX

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Half map: half-map 2 post Bayesian polishing

Fileemd_10273_half_map_2.map
Annotationhalf-map 2 post Bayesian polishing
Projections & Slices
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Sample components

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Entire : human insulin receptor ectodomain bound to four insulin

EntireName: human insulin receptor ectodomain bound to four insulin
Components
  • Complex: human insulin receptor ectodomain bound to four insulin
    • Complex: human insulin receptor ectodomain bound to four insulin
      • Protein or peptide: Insulin receptor
      • Protein or peptide: Insulin receptor
    • Complex: human insulin receptor ectodomain bound to four insulin
      • Protein or peptide: Insulin
      • Protein or peptide: Insulin

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Supramolecule #1: human insulin receptor ectodomain bound to four insulin

SupramoleculeName: human insulin receptor ectodomain bound to four insulin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 375 KDa

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Supramolecule #2: human insulin receptor ectodomain bound to four insulin

SupramoleculeName: human insulin receptor ectodomain bound to four insulin
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: human insulin receptor ectodomain bound to four insulin

SupramoleculeName: human insulin receptor ectodomain bound to four insulin
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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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: Homo sapiens (human)
Molecular weightTheoretical: 82.551742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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 VFVPRPS

UniProtKB: Insulin receptor

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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: Homo sapiens (human)
Molecular weightTheoretical: 18.5139 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
HRPFEKVVNK ESLVISGLRH FTGYRIELQA CNQDTPEERC SVAAYVSART MPEAKADDIV GPVTHEIFEN NVVHLMWQEP KEPNGLIVL YEVSYRRYGD EELHLCVSRK HFALERGCRL RGLSPGNYSV RIRATSLAGN GSWTEPTYFY VTDYLDVPSN I AK

UniProtKB: Insulin receptor

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Macromolecule #3: Insulin

MacromoleculeName: Insulin / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.383698 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString:
GIVEQCCTSI CSLYQLENYC N

UniProtKB: Insulin

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Macromolecule #4: Insulin

MacromoleculeName: Insulin / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.433953 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString:
FVNQHLCGSH LVEALYLVCG ERGFFYTPKT

UniProtKB: Insulin

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 51 / Average exposure time: 10.2 sec. / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 326257
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final 3D classificationSoftware - Name: RELION (ver. 3.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6ceb


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6sof:
human insulin receptor ectodomain bound by 4 insulin

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