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- EMDB-41886: Structure of the HER2/HER4/NRG1b Heterodimer Extracellular Domain -

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Basic information

Entry
Database: EMDB / ID: EMD-41886
TitleStructure of the HER2/HER4/NRG1b Heterodimer Extracellular Domain
Map data
Sample
  • Complex: Ternary complex of HER2/HER4/NRG1b
    • Protein or peptide: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsReceptor Tyrosine Kinase / MEMBRANE PROTEIN / TRANSFERASE
Function / homology
Function and homology information


ERBB3 signaling pathway / sequestering of metal ion / establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / ventricular cardiac muscle cell differentiation / positive regulation of striated muscle cell differentiation / neuregulin receptor activity ...ERBB3 signaling pathway / sequestering of metal ion / establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / ventricular cardiac muscle cell differentiation / positive regulation of striated muscle cell differentiation / neuregulin receptor activity / animal organ development / negative regulation of secretion / positive regulation of peptidyl-tyrosine autophosphorylation / cardiac muscle tissue regeneration / negative regulation of immature T cell proliferation in thymus / endocardial cell differentiation / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / mitochondrial fragmentation involved in apoptotic process / neural crest cell development / cardiac muscle cell myoblast differentiation / semaphorin receptor complex / cell communication / GABA receptor binding / PI3K events in ERBB4 signaling / cardiac muscle cell differentiation / mammary gland epithelial cell differentiation / embryonic pattern specification / mammary gland development / ventricular trabecula myocardium morphogenesis / positive regulation of protein localization to cell surface / chemorepellent activity / regulation of microtubule-based process / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / regulation of postsynaptic neurotransmitter receptor internalization / neurotransmitter receptor localization to postsynaptic specialization membrane / activation of transmembrane receptor protein tyrosine kinase activity / ERBB signaling pathway / epidermal growth factor receptor activity / neural crest cell migration / negative regulation of cardiac muscle cell apoptotic process / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / positive regulation of Rho protein signal transduction / epidermal growth factor receptor binding / neuromuscular junction development / ERBB2 Activates PTK6 Signaling / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / enzyme-linked receptor protein signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / positive regulation of transcription by RNA polymerase I / Signaling by ERBB4 / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / cell surface receptor signaling pathway via JAK-STAT / Long-term potentiation / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion / SHC1 events in ERBB4 signaling / GABA-ergic synapse / mammary gland alveolus development / cell fate commitment / regulation of angiogenesis / coreceptor activity / Schwann cell development / Nuclear signaling by ERBB4 / regulation of cell migration / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of cardiac muscle cell proliferation / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / synapse assembly / Downregulation of ERBB4 signaling / myelination / lactation / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / Downregulation of ERBB2:ERBB3 signaling / activation of protein kinase B activity / transmembrane receptor protein tyrosine kinase activity / neurogenesis
Similarity search - Function
Neuregulin, C-terminal / Neuregulin-1 / Neuregulin / Neuregulin intracellular region / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain ...Neuregulin, C-terminal / Neuregulin-1 / Neuregulin / Neuregulin intracellular region / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / EGF-like domain / Furin-like repeat / Furin-like repeats / Immunoglobulin I-set / Immunoglobulin I-set domain / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / 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
Receptor tyrosine-protein kinase erbB-2 / Pro-neuregulin-1, membrane-bound isoform / Receptor tyrosine-protein kinase erbB-4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsTrenker R / Diwanji D / Bingham T / Verba KA / Jura N
Funding support Germany, United States, 3 items
OrganizationGrant numberCountry
German Research Foundation (DFG)TR 1668/1-1 Germany
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM139636 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA274502 United States
CitationJournal: To Be Published
Title: Structure of the HER2/HER4/NRG1b Heterodimer Extracellular Domain
Authors: Trenker R / Diwanji D / Bingham T / Verba KA / Jura N
History
DepositionSep 10, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41886.png

Downloads & links

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Map

FileDownload / File: emd_41886.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 384 pix.
= 320.64 Å		0.84 Å/pix.
x 384 pix.
= 320.64 Å		0.84 Å/pix.
x 384 pix.
= 320.64 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0464
Minimum - Maximum-0.9736661 - 1.7285682
Average (Standard dev.)-0.000041642543 (±0.027535614)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 320.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41886_msk_1.map
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Half map: #2

Fileemd_41886_half_map_1.map
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Half map: #1

Fileemd_41886_half_map_2.map
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Sample components

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Entire : Ternary complex of HER2/HER4/NRG1b

EntireName: Ternary complex of HER2/HER4/NRG1b
Components
  • Complex: Ternary complex of HER2/HER4/NRG1b
    • Protein or peptide: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Ternary complex of HER2/HER4/NRG1b

SupramoleculeName: Ternary complex of HER2/HER4/NRG1b / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4

MacromoleculeName: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.909648 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVCAGTENK LSSLSDLEQQ YRALRKYYEN CEVVMGNLEI TSIEHNRDLS FLRSVREVTG YVLVALNQFR YLPLENLRII RGTKLYEDR YALAIFLNYR KDGNFGLQEL GLKNLTEILN GGVYVDQNKF LCYADTIHWQ DIVRNPWPSN LTLVSTNGSS G CGRCHKSC ...String:
QSVCAGTENK LSSLSDLEQQ YRALRKYYEN CEVVMGNLEI TSIEHNRDLS FLRSVREVTG YVLVALNQFR YLPLENLRII RGTKLYEDR YALAIFLNYR KDGNFGLQEL GLKNLTEILN GGVYVDQNKF LCYADTIHWQ DIVRNPWPSN LTLVSTNGSS G CGRCHKSC TGRCWGPTEN HCQTLTRTVC AEQCDGRCYG PYVSDCCHRE CAGGCSGPKD TDCFACMNFN DSGACVTQCP QT FVYNPTT FQLEHNFNAK YTYGAFCVKK CPHNFVVDSS SCVRACPSSK MEVEENGIKM CKPCTDICPK ACDGIGTGSL MSA QTVDSS NIDKFINCTK INGNLIFLVT GIHGDPYNAI EAIDPEKLNV FRTVREITGF LNIQSWPPNM TDFSVFSNLV TIGG RVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RKAENCTAEG MVCNH LCSS DGCWGPGPDQ CLSCRRFSRG RICIESCNLY DGEFREFENG SICVECDPQC EKMEDGLLTC HGPGPDNCTK CSHFKD GPN CVEKCPDGLQ GANSFIFKYA DPDRECHPCH PNCTQGCNGP TSHDCI

UniProtKB: Receptor tyrosine-protein kinase erbB-4

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Macromolecule #2: Receptor tyrosine-protein kinase erbB-2

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.888008 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVCTGTDMKL RLPASPETHL DMLRHLYQGC QVVQGNLELT YLPTNASLSF LQDIQEVQGY VLIAHNQVRQ VPLQRLRIVR GTQLFEDNY ALAVLDNGDP LNNTTPVTGA SPGGLRELQL RSLTEILKGG VLIQRNPQLC YQDTILWKDI FHKNNQLALT L IDTNRSRA ...String:
QVCTGTDMKL RLPASPETHL DMLRHLYQGC QVVQGNLELT YLPTNASLSF LQDIQEVQGY VLIAHNQVRQ VPLQRLRIVR GTQLFEDNY ALAVLDNGDP LNNTTPVTGA SPGGLRELQL RSLTEILKGG VLIQRNPQLC YQDTILWKDI FHKNNQLALT L IDTNRSRA CHPCSPMCKG SRCWGESSED CQSLTRTVCA GGCARCKGPL PTDCCHEQCA AGCTGPKHSD CLACLHFNHS GI CELHCPA LVTYNTDTFE SMPNPEGRYT FGASCVTACP YNYLSTDVGS CTLVCPLHNQ EVTAEDGTQR CEKCSKPCAR VCY GLGMEH LREVRAVTSA NIQEFAGCKK IFGSLAFLPE SFDGDPASNT APLQPEQLQV FETLEEITGY LYISAWPDSL PDLS VFQNL QVIRGRILHN GAYSLTLQGL GISWLGLRSL RELGSGLALI HHNTHLCFVH TVPWDQLFRN PHQALLHTAN RPEDE CVGE GLACHQLCAR GHCWGPGPTQ CVNCSQFLRG QECVEECRVL QGLPREYVNA RHCLPCHPEC QPQNGSVTCF GPEADQ CVA CAHYKDPPFC VARCPSGVKP DLSYMPIWKF PDEEGACQPC PIN

UniProtKB: Receptor tyrosine-protein kinase erbB-2

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Macromolecule #3: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform

MacromoleculeName: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.890792 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
SHLVKCAEKE KTFCVNGGEC FMVKDLSNPS RYLCKCPNEF TGDRCQNYVM AS

UniProtKB: Pro-neuregulin-1, membrane-bound isoform

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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: 3 / 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: 7.4
Component:
ConcentrationNameFormula
50.0 mMTris
150.0 mMsodium chlorideNaClSodium chloride
0.5 mMDDM
GridModel: Quantifoil R1.2/1.3 / Support film - Material: GRAPHENE OXIDE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS 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: 0.9 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Average electron dose: 45.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7mn5


Details: Model assembled using 7MN5 and 3U7U
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 289192
FSC plot (resolution estimation)

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