[English] 日本語
Yorodumi
- EMDB-43280: Cryo-EM structure of short form insulin receptor (IR-A) with thre... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-43280
TitleCryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
Map dataCryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
Sample
  • Complex: Short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
    • Protein or peptide: Isoform Short of Insulin receptor
    • Protein or peptide: Insulin-like growth factor IIInsulin-like growth factor 2
KeywordsInsulin receptor / IGF2 / RTK / SIGNALING PROTEIN
Function / homology
Function and homology information


spongiotrophoblast cell proliferation / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / regulation of female gonad development / genomic imprinting / positive regulation of meiotic cell cycle ...spongiotrophoblast cell proliferation / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / regulation of female gonad development / genomic imprinting / positive regulation of meiotic cell cycle / positive regulation of organ growth / 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 / positive regulation of multicellular organism growth / insulin receptor activity / positive regulation of protein-containing complex disassembly / cargo receptor activity / positive regulation of vascular endothelial cell proliferation / dendritic spine maintenance / insulin binding / PTB domain binding / neuronal cell body membrane / adrenal gland development / Signaling by Insulin receptor / IRS activation / positive regulation of activated T cell proliferation / transmembrane receptor protein tyrosine kinase activator activity / amyloid-beta clearance / activation of protein kinase activity / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / positive regulation of cell division / transport across blood-brain barrier / insulin receptor substrate binding / embryonic placenta development / epidermis development / positive regulation of glycogen biosynthetic process / SHC-related events triggered by IGF1R / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of insulin receptor signaling pathway / dendrite membrane / striated muscle cell differentiation / Insulin receptor recycling / insulin-like growth factor receptor binding / receptor-mediated endocytosis / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / protein serine/threonine kinase activator activity / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / learning / caveola / positive regulation of glucose import / animal organ morphogenesis / growth factor activity / positive regulation of MAP kinase activity / insulin receptor binding / hormone activity / receptor internalization / receptor protein-tyrosine kinase / memory / cellular response to growth factor stimulus / osteoblast differentiation / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / male gonad development / cell surface receptor protein tyrosine kinase signaling pathway / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / positive regulation of peptidyl-tyrosine phosphorylation / integrin binding / late endosome / glucose homeostasis / Platelet degranulation / insulin receptor signaling pathway / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / lysosome / receptor ligand activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / carbohydrate metabolic process / positive regulation of cell migration / positive regulation of protein phosphorylation
Similarity search - Function
Insulin-like growth factor II E-peptide, C-terminal / Insulin-like growth factor II / Insulin-like growth factor II E-peptide / Insulin-like growth factor / 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 family ...Insulin-like growth factor II E-peptide, C-terminal / Insulin-like growth factor II / Insulin-like growth factor II E-peptide / Insulin-like growth factor / 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 family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / 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 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
Insulin-like growth factor II / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsAn W / Hall C / Li J / Huang A / Wu J / Park J / Bai XC / Choi E
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM136976 United States
CitationJournal: Nat Commun / Year: 2024
Title: Activation of the insulin receptor by insulin-like growth factor 2.
Authors: Weidong An / Catherine Hall / Jie Li / Albert Hung / Jiayi Wu / Junhee Park / Liwei Wang / Xiao-Chen Bai / Eunhee Choi /
Abstract: Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular ...Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.
History
DepositionJan 6, 2024-
Header (metadata) releaseMar 27, 2024-
Map releaseMar 27, 2024-
UpdateApr 3, 2024-
Current statusApr 3, 2024Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_43280.png

Downloads & links

-
Map

FileDownload / File: emd_43280.map.gz / Format: CCP4 / Size: 75.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.006
Minimum - Maximum-0.021379514 - 0.041689128
Average (Standard dev.)0.0000003397909 (±0.0011691188)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions270270270
Spacing270270270
CellA=B=C: 291.6 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Half map: Cryo-EM structure of short form insulin receptor (IR-A)...

Fileemd_43280_half_map_1.map
AnnotationCryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation. Half map 2.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: Cryo-EM structure of short form insulin receptor (IR-A)...

Fileemd_43280_half_map_2.map
AnnotationCryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation. Half map 1.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : Short form insulin receptor (IR-A) with three IGF2 bound, asymmet...

EntireName: Short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
Components
  • Complex: Short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
    • Protein or peptide: Isoform Short of Insulin receptor
    • Protein or peptide: Insulin-like growth factor IIInsulin-like growth factor 2

-
Supramolecule #1: Short form insulin receptor (IR-A) with three IGF2 bound, asymmet...

SupramoleculeName: Short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

-
Macromolecule #1: Isoform Short of Insulin receptor

MacromoleculeName: Isoform Short of 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: 155.329094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE ...String:
MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE DNYIVLNKDD NEECGDICPG TAKGKTNCPA TVINGQFVER CWTHSHCQKV CPTICKSHGC TAEGLCCHSE CL GNCSQPD DPTKCVACRN FYLDGRCVET CPPPYYHFQD WRCVNFSFCQ DLHHKCKNSR RQGCHQYVIH NNKCIPECPS GYT MNSSNL LCTPCLGPCP KVCHLLEGEK TIDSVTSAQE LRGCTVINGS LIINIRGGNN LAAELEANLG LIEEISGYLK IRRS YALVS LSFFRKLRLI RGETLEIGNY SFYALDNQNL RQLWDWSKHN LTITQGKLFF HYNPKLCLSE IHKMEEVSGT KGRQE RNDI ALKTNGDQAS CENELLKFSY IRTSFDKILL RWEPYWPPDF RDLLGFMLFY KEAPYQNVTE FDGQDACGSN SWTVVD IDP PLRSNDPKSQ NHPGWLMRGL KPWTQYAIFV KTLVTFSDER RTYGAKSDII YVQTDATNPS VPLDPISVSN SSSQIIL KW KPPSDPNGNI THYLVFWERQ AEDSELFELD YCLKGLKLPS RTWSPPFESE DSQKHNQSEY EDSAGECCSC PKTDSQIL K ELEESSFRKT FEDYLHNVVF VPRPSRKRRS LGDVGNVTVA VPTVAAFPNT SSTSVPTSPE EHRPFEKVVN KESLVISGL RHFTGYRIEL QACNQDTPEE RCSVAAYVSA RTMPEAKADD IVGPVTHEIF ENNVVHLMWQ EPKEPNGLIV LYEVSYRRYG DEELHLCVS RKHFALERGC RLRGLSPGNY SVRIRATSLA GNGSWTEPTY FYVTDYLDVP SNIAKIIIGP LIFVFLFSVV I GSIYLFLR KRQPDGPLGP LYASSNPEYL SASDVFPCSV YVPDEWEVSR EKITLLRELG QGSFGMVYEG NARDIIKGEA ET RVAVKTV NESASLRERI EFLNEASVMK GFTCHHVVRL LGVVSKGQPT LVVMELMAHG DLKSYLRSLR PEAENNPGRP PPT LQEMIQ MAAEIADGMA YLNAKKFVHR DLAARNCMVA HDFTVKIGDF GMTRDIYETD YYRKGGKGLL PVRWMAPESL KDGV FTTSS DMWSFGVVLW EITSLAEQPY QGLSNEQVLK FVMDGGYLDQ PDNCPERVTD LMRMCWQFNP KMRPTFLEIV NLLKD DLHP SFPEVSFFHS EENKAPESEE LEMEFEDMEN VPLDRSSHCQ REEAGGRDGG SSLGFKRSYE EHIPYTHMNG GKKNGR ILT LPRSNPS

UniProtKB: Insulin receptor

-
Macromolecule #2: Insulin-like growth factor II

MacromoleculeName: Insulin-like growth factor II / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.170398 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGIPMGKSML VLLTFLAFAS CCIAAYRPSE TLCGGELVDT LQFVCGDRGF YFSRPASRVS RRSRGIVEEC CFRSCDLALL ETYCATPAK SERDVSTPPT VLPDNFPRYP VGKFFQYDTW KQSTQRLRRG LPALLRARRG HVLAKELEAF REAKRHRPLI A LPTQDPAH GGAPPEMASN RK

UniProtKB: Insulin-like growth factor II

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

-
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
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
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

-
Image processing

Particle selectionNumber selected: 3422813
Startup modelType of model: OTHER
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 79813

-
Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8vjc:
Cryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more