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- EMDB-26364: Head region of insulin receptor ectodomain (A-isoform) bound to t... -

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Basic information

Entry
Database: EMDB / ID: EMD-26364
TitleHead region of insulin receptor ectodomain (A-isoform) bound to the non-insulin agonist IM462
Map dataHalf-map 2 of head region of insulin receptor, leucine-zippered form, bound to insulin receptor peptide IM462
Sample
  • Complex: Complex of IM462 with insulin and Fv 83-7 bound to insulin receptor, delta beta, leucine zippered form
    • Protein or peptide: Insulin A chain
    • Protein or peptide: Insulin B chain
    • Protein or peptide: Isoform Short of Insulin receptor
    • Protein or peptide: IM462
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / Insulin processing / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / regulation of protein secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / Insulin processing / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / alpha-beta T cell activation / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / negative regulation of protein secretion / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / positive regulation of nitric oxide mediated signal transduction / fatty acid homeostasis / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / neuron projection maintenance / positive regulation of brown fat cell differentiation / endoplasmic reticulum-Golgi intermediate compartment membrane / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / Regulation of insulin secretion / positive regulation of long-term synaptic potentiation / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of protein secretion / positive regulation of nitric-oxide synthase activity / regulation of transmembrane transporter activity / positive regulation of cell differentiation / positive regulation of glucose import / negative regulation of proteolysis / regulation of synaptic plasticity / wound healing / insulin receptor binding / hormone activity / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / cognition / positive regulation of neuron projection development / Golgi lumen / positive regulation of protein localization to nucleus / vasodilation / glucose metabolic process / regulation of protein localization / glucose homeostasis / cell-cell signaling / insulin receptor signaling pathway / positive regulation of NF-kappaB transcription factor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / secretory granule lumen / protease binding / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Insulin / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / Insulin-like superfamily
Similarity search - Domain/homology
Insulin / Isoform Short of Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsKirk NS / Lawrence MC
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nat Commun / Year: 2022
Title: Activation of the human insulin receptor by non-insulin-related peptides.
Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David ...Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David G Barrett / Michael C Lawrence /
Abstract: The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in ...The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from-but related to-those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics.
History
DepositionMar 3, 2022-
Header (metadata) releaseOct 5, 2022-
Map releaseOct 5, 2022-
UpdateOct 5, 2022-
Current statusOct 5, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26364.png

Downloads & links

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Map

FileDownload / File: emd_26364.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHalf-map 2 of head region of insulin receptor, leucine-zippered form, bound to insulin receptor peptide IM462
Voxel sizeX=Y=Z: 1.41333 Å
Density
Contour LevelBy AUTHOR: 0.037
Minimum - Maximum-0.09051475 - 0.16728361
Average (Standard dev.)5.3478718e-05 (±0.0016585103)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 407.03992 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half-map 1 of head region of insulin receptor,...

Fileemd_26364_half_map_1.map
AnnotationHalf-map 1 of head region of insulin receptor, leucine-zippered form, bound to insulin receptor peptide IM462
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map 1 of head region of insulin receptor,...

Fileemd_26364_half_map_2.map
AnnotationHalf-map 1 of head region of insulin receptor, leucine-zippered form, bound to insulin receptor peptide IM462
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of IM462 with insulin and Fv 83-7 bound to insulin recept...

EntireName: Complex of IM462 with insulin and Fv 83-7 bound to insulin receptor, delta beta, leucine zippered form
Components
  • Complex: Complex of IM462 with insulin and Fv 83-7 bound to insulin receptor, delta beta, leucine zippered form
    • Protein or peptide: Insulin A chain
    • Protein or peptide: Insulin B chain
    • Protein or peptide: Isoform Short of Insulin receptor
    • Protein or peptide: IM462
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of IM462 with insulin and Fv 83-7 bound to insulin recept...

SupramoleculeName: Complex of IM462 with insulin and Fv 83-7 bound to insulin receptor, delta beta, leucine zippered form
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Insulin A chain

MacromoleculeName: Insulin A chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.383698 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString:
GIVEQCCTSI CSLYQLENYC N

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Macromolecule #2: Insulin B chain

MacromoleculeName: Insulin B chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.433953 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString:
FVNQHLCGSH LVEALYLVCG ERGFFYTPKT

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Macromolecule #3: Isoform Short of Insulin receptor

MacromoleculeName: Isoform Short of Insulin receptor / type: protein_or_peptide / ID: 3 / Details: delta beta construct, leucine-zippered form / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 106.728211 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNHIVLNK DDNEECGDIC P GTAKGKTN ...String:
HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNHIVLNK 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 KHNLTTTQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDK 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 VFVPRPSR K RRSLGDVGNA GNNEEHRPFE KVVNKESLVI SGLRHFTGYR IELQACNQDT PEERCSVAAY VSARTMPEAK ADDIVGPVT HEIFENNVVH LMWQEPKEPN GLIVLYEVSY RRYGDEELHL CVSRKHFALE RGCRLRGLSP GNYSVRIRAT SLAGNGSWTE PTYFYVTDY LDVPSNIARM KQLEDKVEEL LSKNYHLENE VARLKKLVGE R

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Macromolecule #4: IM462

MacromoleculeName: IM462 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 2.644862 KDa
SequenceString:
(HY1)SLEEEWAQI ECEVYGRCPP SES

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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: 8
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: 2.0 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K3 (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

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 346000

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