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- PDB-4hrm: Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexp... -

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Basic information

Entry
Database: PDB / ID: 4hrm
TitleStructural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via Binding to the Extracellular Domain of HER2
Components
  • Designed Ankyrin Repeat Protein 9_26
  • Domain I of receptor tyrosine-protein kinase erbB-2
KeywordsTRANSFERASE/DE NOVO PROTEIN / TRANSFERASE-DE NOVO PROTEIN complex
Function / homology
Function and homology information


negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / RNA polymerase I core binding / immature T cell proliferation in thymus / semaphorin receptor complex / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse ...negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / RNA polymerase I core binding / immature T cell proliferation in thymus / semaphorin receptor complex / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse / regulation of microtubule-based process / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2 Activates PTK6 Signaling / enzyme-linked receptor protein signaling pathway / neuromuscular junction development / positive regulation of Rho protein signal transduction / ERBB2-ERBB3 signaling pathway / 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 / positive regulation of MAP kinase activity / positive regulation of transcription by RNA polymerase I / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / oligodendrocyte differentiation / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / Schwann cell development / coreceptor activity / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / transmembrane receptor protein tyrosine kinase activity / positive regulation of cell adhesion / GRB2 events in ERBB2 signaling / Downregulation of ERBB2:ERBB3 signaling / SHC1 events in ERBB2 signaling / cell surface receptor protein tyrosine kinase signaling pathway / basal plasma membrane / peptidyl-tyrosine phosphorylation / cellular response to epidermal growth factor stimulus / Constitutive Signaling by Overexpressed ERBB2 / positive regulation of translation / positive regulation of epithelial cell proliferation / neuromuscular junction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / Signaling by ERBB2 TMD/JMD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / receptor tyrosine kinase binding / Signaling by ERBB2 KD Mutants / cellular response to growth factor stimulus / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / heart development / presynaptic membrane / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / early endosome / cell surface receptor signaling pathway / cell population proliferation / protein phosphorylation / receptor complex / endosome membrane / positive regulation of MAPK cascade / intracellular signal transduction / apical plasma membrane / protein heterodimerization activity / signaling receptor binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane / plasma membrane / cytosol
Similarity search - Function
24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / Ankyrin repeat-containing domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Alpha-Beta Horseshoe / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain ...24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / Ankyrin repeat-containing domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Alpha-Beta Horseshoe / 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 / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / : / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / 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. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.2 Å
AuthorsJost, C. / Schilling, J. / Plueckthun, A.
CitationJournal: Structure / Year: 2013
Title: Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via Binding to the Extracellular Domain of HER2.
Authors: Jost, C. / Schilling, J. / Tamaskovic, R. / Schwill, M. / Honegger, A. / Plueckthun, A.
History
DepositionOct 28, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 16, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2013Group: Structure summary
Revision 1.2Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Domain I of receptor tyrosine-protein kinase erbB-2
A: Domain I of receptor tyrosine-protein kinase erbB-2
B: Designed Ankyrin Repeat Protein 9_26
D: Designed Ankyrin Repeat Protein 9_26


Theoretical massNumber of molelcules
Total (without water)81,7134
Polymers81,7134
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)138.500, 60.700, 107.200
Angle α, β, γ (deg.)90.000, 118.900, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Domain I of receptor tyrosine-protein kinase erbB-2 / Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / ...Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / Tyrosine kinase-type cell surface receptor HER2 / p185erbB2


Mass: 22208.281 Da / Num. of mol.: 2
Fragment: N-terminal extracellular domain I, UNP RESIDUES 24-219
Mutation: N46D, N102D, N165D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB2, HER2, MLN19, NEU, NGL / Plasmid: pFL / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04626, receptor protein-tyrosine kinase
#2: Protein Designed Ankyrin Repeat Protein 9_26


Mass: 18648.033 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic (others) / Plasmid: pQE30 / Production host: Escherichia coli (E. coli) / Strain (production host): XL1-blue
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 49.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.2
Details: 0.2 M sodium chloride, 0.1 M phosphate citrate, 20% PEG 8000, pH 4.2, vapor diffusion, temperature 293K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: PSI PILATUS 2M / Detector: PIXEL / Date: Jan 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionHighest resolution: 3.2 Å / Num. obs: 12785 / % possible obs: 97.2 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 32.57 Å2 / Rmerge(I) obs: 0.071 / Net I/σ(I): 14.37
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
3.2-3.280.2980.2085.9429729699530.25198.3
3.28-3.370.3050.1946.2928359349200.23698.5
3.37-3.470.2450.1587.4526939118900.19297.7
3.47-3.580.2050.138.6125968948770.15998.1
3.58-3.70.1790.1238.9523678508270.15397.3
3.7-3.820.1370.08911.1121658308020.11196.6
3.82-3.970.1230.07511.9220658117690.09494.8
3.97-4.130.120.07513.2719717627270.09495.4
4.13-4.310.10.06315.4121197427190.07896.9
4.31-4.530.0750.05417.8320857086920.06697.7
4.53-4.770.0650.05318.5820727006700.06495.7
4.77-5.060.0630.0518.5419386486340.06197.8
5.06-5.410.0930.06216.417826035870.07697.3
5.41-5.840.0950.07314.6516725575480.08998.4
5.84-6.40.0930.06316.9115135215070.07797.3
6.4-7.160.0750.05117.5912914754660.06398.1
7.16-8.260.0440.03523.5210944244110.04496.9
8.26-10.120.0250.02536.9811023613550.03198.3
10.12-14.310.0220.02141.678842832760.02597.5
14.310.020.02342.684681681550.02892.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.2 Å43.12 Å
Translation3.2 Å43.12 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER2.3.0phasing
PHENIX1.8_1069refinement
PDB_EXTRACT3.11data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1N8Z, 2XEE

1n8z

2xee


Resolution: 3.2→43.117 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7071 / SU ML: 0.56 / σ(F): 1.99 / Phase error: 35.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3385 621 4.86 %
Rwork0.3139 12151 -
obs0.3151 12772 97.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.55 Å2 / Biso mean: 48.6592 Å2 / Biso min: 4.6 Å2
Refinement stepCycle: LAST / Resolution: 3.2→43.117 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3517 0 0 0 3517
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043541
X-RAY DIFFRACTIONf_angle_d0.7654831
X-RAY DIFFRACTIONf_chiral_restr0.045632
X-RAY DIFFRACTIONf_plane_restr0.004634
X-RAY DIFFRACTIONf_dihedral_angle_d13.5971038
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.2001-3.5220.41191530.33373019317298
3.522-4.03130.36581560.31122995315197
4.0313-5.07770.30631520.29583023317597
5.0777-43.12090.30871600.32283114327498

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