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

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Basic information

Entry
Database: PDB / ID: 4hrn
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 H10-2-G
  • 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
Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / Ankyrin repeat-containing domain / : / 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 ...Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / Ankyrin repeat-containing domain / : / 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 / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / : / Ribbon / 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 Beta / Mainly Alpha
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciessynthetic (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.65 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 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Designed Ankyrin Repeat Protein H10-2-G
B: Designed Ankyrin Repeat Protein H10-2-G
C: Receptor tyrosine-protein kinase erbB-2
D: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)52,5534
Polymers52,5534
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4740 Å2
ΔGint-31 kcal/mol
Surface area16150 Å2
MethodPISA
2
A: Designed Ankyrin Repeat Protein H10-2-G
D: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)26,2772
Polymers26,2772
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1520 Å2
ΔGint-10 kcal/mol
Surface area8820 Å2
MethodPISA
3
B: Designed Ankyrin Repeat Protein H10-2-G
C: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)26,2772
Polymers26,2772
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint-11 kcal/mol
Surface area9140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)195.000, 195.000, 112.000
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32

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Components

#1: Protein Designed Ankyrin Repeat Protein H10-2-G


Mass: 14618.437 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
#2: Protein 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: 11658.186 Da / Num. of mol.: 2 / Fragment: Domain IV, UNP RESIDUES 529-625 / Mutation: N8D, N49D
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
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: 3.9 Å3/Da / Density % sol: 68.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4
Details: 0.05M succinic acid, 29% ammonium sulfate, pH 4.0, vapor diffusion, temperature 293K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Aug 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionHighest resolution: 2.65 Å / Num. obs: 23767 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 64.811 Å2 / Rmerge(I) obs: 0.041 / Net I/σ(I): 26.42
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
2.65-2.720.6270.5113.548239173617350.57599.9
2.72-2.790.4710.3824.638448171117110.428100
2.79-2.870.3780.3215.828674166516620.35899.8
2.87-2.960.2330.2227.988481160116010.247100
2.96-3.060.1880.16410.388174155115490.18399.9
3.06-3.170.1460.12912.877931150915080.14499.9
3.17-3.290.1010.09716.377596145814580.108100
3.29-3.420.0720.06820.837040139313930.076100
3.42-3.570.0550.05125.556492136313630.057100
3.57-3.750.0390.04131.186514130513030.04699.8
3.75-3.950.0280.03537.786474121212120.039100
3.95-4.190.0230.0342.956051115211510.03399.9
4.19-4.480.0210.02845.875647109710970.031100
4.48-4.840.0190.02746.095144102510250.03100
4.84-5.30.0190.02547.8643459409390.02899.9
5.3-5.930.0180.02550.2243598658640.02899.9
5.93-6.840.0160.02256.3238917507490.02499.9
6.84-8.380.0110.01869.4732426516490.0299.7
8.38-11.850.010.01772.2522845115090.01999.6
11.850.010.01677.3914292962890.01897.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.65 Å48.75 Å
Translation2.65 Å48.75 Å

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Processing

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

1n8z

2jab


Resolution: 2.65→48.75 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.31 / σ(F): 1.99 / Phase error: 30.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2494 1218 5.13 %
Rwork0.2177 --
obs0.2194 23756 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 86.21 Å2 / Biso mean: 47.5965 Å2 / Biso min: 27.12 Å2
Refinement stepCycle: LAST / Resolution: 2.65→48.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2808 0 0 0 2808

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