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- PDB-6op9: HER3 pseudokinase domain bound to bosutinib -

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Basic information

Entry
Database: PDB / ID: 6op9
TitleHER3 pseudokinase domain bound to bosutinib
ComponentsReceptor tyrosine-protein kinase erbB-3
KeywordsTRANSFERASE/TRANSFERASE inhibitor / RECEPTOR TYROSINE KINASE / PSEUDOKINASE / BOSUTINIB / MEMBRANE / SIGNALING PROTEIN / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / ERBB3:ERBB2 complex / GRB7 events in ERBB2 signaling / positive regulation of calcineurin-NFAT signaling cascade ...neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / ERBB3:ERBB2 complex / GRB7 events in ERBB2 signaling / positive regulation of calcineurin-NFAT signaling cascade / peripheral nervous system development / ErbB-3 class receptor binding / negative regulation of cell adhesion / negative regulation of motor neuron apoptotic process / motor neuron apoptotic process / ERBB2 Activates PTK6 Signaling / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / Signaling by ERBB4 / growth factor binding / ERBB2 Regulates Cell Motility / PI3K events in ERBB2 signaling / lateral plasma membrane / Schwann cell development / negative regulation of signal transduction / extrinsic apoptotic signaling pathway in absence of ligand / Signaling by ERBB2 / myelination / Downregulation of ERBB2:ERBB3 signaling / SHC1 events in ERBB2 signaling / neurogenesis / basal plasma membrane / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor protein tyrosine kinase signaling pathway / Signaling by ERBB2 TMD/JMD mutants / wound healing / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / heart development / regulation of cell population proliferation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / basolateral plasma membrane / neuron apoptotic process / negative regulation of neuron apoptotic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein kinase activity / apical plasma membrane / protein heterodimerization activity / phosphorylation / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / signal transduction / extracellular space / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
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 ...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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-DB8 / Receptor tyrosine-protein kinase erbB-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.501 Å
AuthorsLittlefield, P. / Agnew, C. / Jura, N.
Funding support United States, 1items
OrganizationGrant numberCountry
American Heart Association1BGIA744005 United States
CitationJournal: Cell Rep / Year: 2022
Title: Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers.
Authors: Campbell, M.R. / Ruiz-Saenz, A. / Peterson, E. / Agnew, C. / Ayaz, P. / Garfinkle, S. / Littlefield, P. / Steri, V. / Oeffinger, J. / Sampang, M. / Shan, Y. / Shaw, D.E. / Jura, N. / Moasser, M.M.
History
DepositionApr 24, 2019Deposition site: RCSB / Processing site: RCSB
SupersessionAug 21, 2019ID: 4OTW
Revision 1.0Aug 21, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4722
Polymers36,9421
Non-polymers5301
Water1,60389
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)116.385, 116.385, 58.194
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Receptor tyrosine-protein kinase erbB-3 / Proto-oncogene-like protein c-ErbB-3 / Tyrosine kinase-type cell surface receptor HER3


Mass: 36941.926 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB3, HER3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P21860, receptor protein-tyrosine kinase
#2: Chemical ChemComp-DB8 / 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile / Bosutinib / Bosutinib


Mass: 530.446 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C26H29Cl2N5O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor, medication*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 89 / Source method: isolated from a natural source / Formula: H2O

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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: 3.08 Å3/Da / Density % sol: 60.06 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.7 / Details: 10% PEG 20000, 0.1M MES, pH 6.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11587 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 6, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11587 Å / Relative weight: 1
ReflectionResolution: 2.501→41.15 Å / Num. obs: 15679 / % possible obs: 98.1 % / Redundancy: 13.4 % / CC1/2: 0.996 / Rmerge(I) obs: 0.141 / Rpim(I) all: 0.039 / Rrim(I) all: 0.147 / Net I/σ(I): 15.5
Reflection shellResolution: 2.501→2.591 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.596 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 1305 / CC1/2: 0.81 / Rpim(I) all: 0.259 / Rrim(I) all: 0.654 / % possible all: 83.1

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.501→41.149 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 20.13
RfactorNum. reflection% reflection
Rfree0.2302 761 4.85 %
Rwork0.1704 --
obs0.1733 15679 98.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.501→41.149 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2124 0 36 89 2249
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082221
X-RAY DIFFRACTIONf_angle_d0.9293026
X-RAY DIFFRACTIONf_dihedral_angle_d8.1971792
X-RAY DIFFRACTIONf_chiral_restr0.05342
X-RAY DIFFRACTIONf_plane_restr0.006378
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5011-2.69420.25361380.19782697X-RAY DIFFRACTION90
2.6942-2.96530.26281470.19743046X-RAY DIFFRACTION100
2.9653-3.39420.25741520.17742995X-RAY DIFFRACTION100
3.3942-4.27560.22921550.15313063X-RAY DIFFRACTION100
4.2756-41.15440.19981690.16373117X-RAY DIFFRACTION100

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