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

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Basic information

Entry
Database: PDB / ID: 4hrl
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_29
  • 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 / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / ErbB-3 class receptor binding / regulation of microtubule-based process / 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 / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / ErbB-3 class receptor binding / regulation of microtubule-based process / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / positive regulation of Rho protein signal transduction / ERBB2 Activates PTK6 Signaling / neuromuscular junction development / positive regulation of transcription by RNA polymerase I / 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 / ERBB2-ERBB3 signaling pathway / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / coreceptor activity / Schwann cell development / cell surface receptor protein tyrosine kinase signaling pathway / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / positive regulation of cell adhesion / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / neurogenesis / positive regulation of epithelial cell proliferation / basal plasma membrane / positive regulation of translation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / neuromuscular junction / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / neuron differentiation / cellular response to growth factor stimulus / receptor tyrosine kinase binding / Downregulation of ERBB2 signaling / peptidyl-tyrosine phosphorylation / ruffle membrane / 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 / protein tyrosine kinase activity / positive regulation of cell growth / basolateral plasma membrane / positive regulation of MAPK cascade / early endosome / receptor complex / cell surface receptor signaling pathway / endosome membrane / intracellular signal transduction / protein heterodimerization activity / positive regulation of protein phosphorylation / protein phosphorylation / apical plasma membrane / signaling receptor binding / positive regulation of cell population proliferation / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / identical protein binding / membrane / nucleus / plasma membrane
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: 2.55 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 16, 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: Receptor tyrosine-protein kinase erbB-2
A: Designed Ankyrin Repeat Protein 9_29


Theoretical massNumber of molelcules
Total (without water)40,7672
Polymers40,7672
Non-polymers00
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1540 Å2
ΔGint-9 kcal/mol
Surface area14650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.600, 80.500, 115.100
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: 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: 22208.281 Da / Num. of mol.: 1
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_29


Mass: 18558.678 Da / Num. of mol.: 1
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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
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: 2.65 Å3/Da / Density % sol: 53.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.6
Details: 0.2M ammonium acetate, 0.1M sodium citrate, 30% PEG 4000, pH 5.6, 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 21, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionHighest resolution: 2.55 Å / Num. obs: 14533 / % possible obs: 98.7 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 40.398 Å2 / Rmerge F obs: 0.119 / Rmerge(I) obs: 0.071 / Rrim(I) all: 0.083 / Net I/σ(I): 17.83 / Num. measured all: 53167
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
2.55-2.620.4780.4074.014045106410580.47199.4
2.62-2.690.4030.3614.833922104310350.41799.2
2.69-2.770.3390.3195.26376610069950.36998.9
2.77-2.850.290.2586.1135589799710.399.2
2.85-2.940.2650.2267.2233729519450.26399.4
2.94-3.050.2250.198.3632879329320.223100
3.05-3.160.1810.1579.9833438968880.18299.1
3.16-3.290.1370.1212.5732708688630.13999.4
3.29-3.440.1030.09315.5730818408280.10798.6
3.44-3.610.0750.06719.7829337907860.07799.5
3.61-3.80.060.05223.8825977457310.06198.1
3.8-4.030.0520.04526.2424557317140.05297.7
4.03-4.310.0350.03533.6925346756670.0498.8
4.31-4.660.0310.03137.0923856496330.03697.5
4.66-5.10.0310.03135.521165885730.03697.4
5.1-5.70.050.04226.7717805355280.0598.7
5.7-6.580.0420.03828.9516564824730.04498.1
6.58-8.060.0250.02443.3214314144040.02897.6
8.06-11.40.0160.01754.8610543353250.0297
11.40.0140.01656.475821991840.01992.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.55 Å46.82 Å
Translation2.55 Å46.82 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: 2.55→46.817 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8233 / SU ML: 0.31 / σ(F): 1.99 / Phase error: 24.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2529 733 5.04 %
Rwork0.2004 13799 -
obs0.203 14532 98.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 77.58 Å2 / Biso mean: 32.9895 Å2 / Biso min: 11.46 Å2
Refinement stepCycle: LAST / Resolution: 2.55→46.817 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2517 0 0 31 2548
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082575
X-RAY DIFFRACTIONf_angle_d1.2933493
X-RAY DIFFRACTIONf_chiral_restr0.109406
X-RAY DIFFRACTIONf_plane_restr0.007461
X-RAY DIFFRACTIONf_dihedral_angle_d15.503914
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.55-2.74690.30681580.22712725288399
2.7469-3.02330.31071460.2322696284299
3.0233-3.46060.27031560.212726288299
3.4606-4.35950.22731430.17382764290799
4.3595-46.82450.22131300.19852888301897

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