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- EMDB-23767: Insulin receptor ectodomain dimer complexed with two IRPA-9 parti... -

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Basic information

Entry
Database: EMDB / ID: EMD-23767
TitleInsulin receptor ectodomain dimer complexed with two IRPA-9 partial agonists
Map dataMain map used for the reconstruction.
Sample
  • Complex: IR-ECD dimer complexed with two IRPA-9 full agonists
    • Complex: IR-ECD dimer
      • Protein or peptide: Isoform Short of Insulin receptor
      • Protein or peptide: Isoform Short of Insulin receptor alpha
    • Complex: IRPA-9 full agonist
      • Protein or peptide: Insulin chain A
      • Protein or peptide: Insulin B chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsInsulin receptor / PEPTIDE BINDING 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 / male sex determination / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / 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 / male sex determination / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / dendritic spine maintenance / cargo receptor activity / insulin binding / negative regulation of NAD(P)H oxidase activity / neuronal cell body membrane / adrenal gland development / PTB domain binding / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / amyloid-beta clearance / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / positive regulation of protein autophosphorylation / regulation of embryonic development / alpha-beta T cell activation / positive regulation of receptor internalization / protein kinase activator activity / insulin receptor substrate binding / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / epidermis development / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / Signal attenuation / fatty acid homeostasis / phosphatidylinositol 3-kinase binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of insulin receptor signaling pathway / negative regulation of lipid catabolic process / transport across blood-brain barrier / regulation of protein localization to plasma membrane / positive regulation of lipid biosynthetic process / heart morphogenesis / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / activation of protein kinase B activity / COPI-mediated anterograde transport / transport vesicle / nitric oxide-cGMP-mediated signaling / negative regulation of reactive oxygen species biosynthetic process / Insulin receptor recycling / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / dendrite membrane / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of MAP kinase activity / positive regulation of nitric-oxide synthase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / regulation of transmembrane transporter activity / positive regulation of glycolytic process / learning / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / endosome lumen / acute-phase response / positive regulation of D-glucose import / positive regulation of protein secretion / positive regulation of cell differentiation / Regulation of insulin secretion / insulin receptor binding / wound healing / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase
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 speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.2 Å
AuthorsGomez-Llorente Y / Zhou H
CitationJournal: Nat Commun / Year: 2022
Title: Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists.
Authors: Margaret Wu / Ester Carballo-Jane / Haihong Zhou / Peter Zafian / Ge Dai / Mindy Liu / Julie Lao / Terri Kelly / Dan Shao / Judith Gorski / Dmitri Pissarnitski / Ahmet Kekec / Ying Chen / ...Authors: Margaret Wu / Ester Carballo-Jane / Haihong Zhou / Peter Zafian / Ge Dai / Mindy Liu / Julie Lao / Terri Kelly / Dan Shao / Judith Gorski / Dmitri Pissarnitski / Ahmet Kekec / Ying Chen / Stephen F Previs / Giovanna Scapin / Yacob Gomez-Llorente / Scott A Hollingsworth / Lin Yan / Danqing Feng / Pei Huo / Geoffrey Walford / Mark D Erion / David E Kelley / Songnian Lin / James Mu /
Abstract: Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, ...Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes.
History
DepositionApr 3, 2021-
Header (metadata) releaseFeb 23, 2022-
Map releaseFeb 23, 2022-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7md5
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23767.png

Downloads & links

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Map

FileDownload / File: emd_23767.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map used for the reconstruction.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 288 pix.
= 299.52 Å		1.04 Å/pix.
x 288 pix.
= 299.52 Å		1.04 Å/pix.
x 288 pix.
= 299.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.33 / Movie #1: 0.3
Minimum - Maximum-0.40882918 - 1.0276213
Average (Standard dev.)0.004975788 (±0.040503733)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 299.52 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z299.520299.520299.520
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-0.4091.0280.005

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Supplemental data

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Mask #1

Fileemd_23767_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A.

Fileemd_23767_half_map_1.map
AnnotationHalf map A.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B.

Fileemd_23767_half_map_2.map
AnnotationHalf map B.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : IR-ECD dimer complexed with two IRPA-9 full agonists

EntireName: IR-ECD dimer complexed with two IRPA-9 full agonists
Components
  • Complex: IR-ECD dimer complexed with two IRPA-9 full agonists
    • Complex: IR-ECD dimer
      • Protein or peptide: Isoform Short of Insulin receptor
      • Protein or peptide: Isoform Short of Insulin receptor alpha
    • Complex: IRPA-9 full agonist
      • Protein or peptide: Insulin chain A
      • Protein or peptide: Insulin B chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: IR-ECD dimer complexed with two IRPA-9 full agonists

SupramoleculeName: IR-ECD dimer complexed with two IRPA-9 full agonists / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Molecular weightTheoretical: 230 KDa

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Supramolecule #2: IR-ECD dimer

SupramoleculeName: IR-ECD dimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: IRPA-9 full agonist

SupramoleculeName: IRPA-9 full agonist / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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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: 106.143359 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
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 VFVPRPSR K RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAY VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRIRAT SLAGNGSWTE PTYFYVTDYL DVPSNIAKHH HHHHHHHH

UniProtKB: Insulin receptor

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Macromolecule #2: Isoform Short of Insulin receptor alpha

MacromoleculeName: Isoform Short of Insulin receptor alpha / 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: 3.459836 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
AAAKELEESS FRKTFEDYLH NVVFVPSPSR

UniProtKB: Insulin receptor

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Macromolecule #3: Insulin chain A

MacromoleculeName: Insulin chain A / 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: Escherichia coli (E. coli)
SequenceString:
GIVEQCCTSI CSLYQLENYC N

UniProtKB: Insulin

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Macromolecule #4: Insulin B chain

MacromoleculeName: Insulin B chain / 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: Escherichia coli (E. coli)
SequenceString:
FVNQHLCGSH LVEALYLVCG ERGFFYTPKT

UniProtKB: Insulin

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.4
GridModel: Homemade / Material: COPPER / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
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 / In silico model: ab-initio from cryoSPARC.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 54293
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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