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- EMDB-25191: Full-length insulin receptor bound with site 2 binding deficient ... -

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Basic information

Entry
Database: EMDB / ID: EMD-25191
TitleFull-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation
Map dataCryo-EM structure of full-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation
Sample
  • Complex: Full-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin B chain
    • Protein or peptide: Insulin A chain
Keywordsinsulin receptor / site 1 binding deficient mutant insulin / SIGNALING PROTEIN / SIGNALING PROTEIN-HORMONE complex
Function / homology
Function and homology information


Signaling by Insulin receptor / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth ...Signaling by Insulin receptor / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 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 / male sex determination / insulin-like growth factor I binding / exocrine pancreas development / nuclear lumen / insulin binding / negative regulation of NAD(P)H oxidase activity / adrenal gland development / negative regulation of glycogen catabolic process / PTB domain binding / negative regulation of feeding behavior / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of protein autophosphorylation / Regulation of gene expression in beta cells / positive regulation of respiratory burst / negative regulation of acute inflammatory response / regulation of embryonic development / alpha-beta T cell activation / positive regulation of receptor internalization / insulin receptor substrate binding / protein kinase activator activity / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / positive regulation of insulin receptor signaling pathway / epidermis development / negative regulation of protein secretion / activation of protein kinase B activity / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / regulation of protein localization to plasma membrane / heart morphogenesis / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / phosphatidylinositol 3-kinase binding / transport vesicle / nitric oxide-cGMP-mediated signaling / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / Insulin receptor recycling / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / insulin receptor activity / regulation of transmembrane transporter activity / positive regulation of glycolytic process / positive regulation of cytokine production / animal organ morphogenesis / positive regulation of long-term synaptic potentiation / endosome lumen / acute-phase response / positive regulation of protein secretion / positive regulation of D-glucose import / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / wound healing / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / hormone activity / regulation of synaptic plasticity / positive regulation of neuron projection development / cellular response to growth factor stimulus / receptor internalization / caveola / positive regulation of protein localization to nucleus / Golgi lumen / cognition / recycling endosome membrane / glucose metabolic process / male gonad development / positive regulation of nitric oxide biosynthetic process / vasodilation / late endosome / insulin receptor signaling pathway
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 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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 speciesMus musculus (house mouse) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.0 Å
AuthorsBai 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 Struct Mol Biol / Year: 2022
Title: Synergistic activation of the insulin receptor via two distinct sites.
Authors: Jie Li / Junhee Park / John P Mayer / Kristofor J Webb / Emiko Uchikawa / Jiayi Wu / Shun Liu / Xuewu Zhang / Michael H B Stowell / Eunhee Choi / Xiao-Chen Bai /
Abstract: Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional ...Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation.
History
DepositionOct 22, 2021-
Header (metadata) releaseMar 30, 2022-
Map releaseMar 30, 2022-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25191.png

Downloads & links

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Map

FileDownload / File: emd_25191.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of full-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.014239215 - 0.04736185
Average (Standard dev.)0.0001109677 (±0.0018321299)
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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Sample components

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Entire : Full-length insulin receptor bound with site 2 binding deficient ...

EntireName: Full-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation
Components
  • Complex: Full-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin B chain
    • Protein or peptide: Insulin A chain

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Supramolecule #1: Full-length insulin receptor bound with site 2 binding deficient ...

SupramoleculeName: Full-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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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: 155.790516 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE ...String:
MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE DNYIVLNKDD NEECGDVCPG TAKGKTNCPA TVINGQFVER CWTHSHCQKV CPTICKSHGC TAEGLCCHKE CL GNCSEPD DPTKCVACRN FYLDGQCVET CPPPYYHFQD WRCVNFSFCQ DLHFKCRNSR KPGCHQYVIH NNKCIPECPS GYT MNSSNL MCTPCLGPCP KVCQILEGEK TIDSVTSAQE LRGCTVINGS LIINIRGGNN LAAELEANLG LIEEISGFLK IRRS YALVS LSFFRKLHLI RGETLEIGNY SFYALDNQNL RQLWDWSKHN LTITQGKLFF HYNPKLCLSE IHKMEEVSGT KGRQE RNDI ALKTNGDQAS CENELLKFSF IRTSFDKILL RWEPYWPPDF RDLLGFMLFY KEAPYQNVTE FDGQDACGSN SWTVVD IDP PQRSNDPKSQ TPSHPGWLMR GLKPWTQYAI FVKTLVTFSD ERRTYGAKSD IIYVQTDATN PSVPLDPISV SNSSSQI IL KWKPPSDPNG NITHYLVYWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SDDSQKHNQS EYDDSASECC SCPKTDSQ I LKELEESSFR KTFEDYLHNV VFVPRPSRKR RSLEEVGNVT ATTLTLPDFP NVSSTIVPTS QEEHRPFEKV VNKESLVIS GLRHFTGYRI ELQACNQDSP DERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRVRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII GPLIFVFLFS V VIGSIYLF LRKRQPDGPM GPLYASSNPE YLSASDVFPS SVYVPDEWEV PREKITLLRE LGQGSFGMVY EGNAKDIIKG EA ETRVAVK TVNESASLRE RIEFLNEASV MKGFTCHHVV RLLGVVSKGQ PTLVVMELMA HGDLKSHLRS LRPDAENNPG RPP PTLQEM IQMTAEIADG MAYLNAKKFV HRDLAARNCM VAHDFTVKIG DFGMTRDIYE TDYYRKGGKG LLPVRWMSPE SLKD GVFTA SSDMWSFGVV LWEITSLAEQ PYQGLSNEQV LKFVMDGGYL DPPDNCPERL TDLMRMCWQF NPKMRPTFLE IVNLL KDDL HPSFPEVSFF YSEENKAPES EELEMEFEDM ENVPLDRSSH CQREEAGGRE GGSSLSIKRT YDEHIPYTHM NGGKKN GRV LTLPRSNPS

UniProtKB: Insulin receptor

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Macromolecule #2: Insulin B chain

MacromoleculeName: Insulin B chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.477989 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
FVNQHLCGSH LVEALYRVCG ERGFFYTPKT

UniProtKB: Insulin

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Macromolecule #3: Insulin A chain

MacromoleculeName: Insulin A chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.383698 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GIVEQCCTSI CSLYQLENYC N

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

Concentration6 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
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: 1704973
Startup modelType of model: OTHER / Details: From RELION3
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 115018
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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