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- PDB-6i8z: Crystal structure of PTK2 in complex with BI-4464. -

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Basic information

Entry
Database: PDB / ID: 6i8z
TitleCrystal structure of PTK2 in complex with BI-4464.
ComponentsFocal adhesion kinase 1
KeywordsTRANSFERASE / Inhibitor / Protein kinase
Function / homology
Function and homology information


netrin-activated signaling pathway / regulation of substrate adhesion-dependent cell spreading / regulation of endothelial cell migration / regulation of epithelial cell migration / detection of muscle stretch / positive regulation of ubiquitin-dependent protein catabolic process / JUN kinase binding / signal complex assembly / positive regulation of macrophage proliferation / positive regulation of fibroblast migration ...netrin-activated signaling pathway / regulation of substrate adhesion-dependent cell spreading / regulation of endothelial cell migration / regulation of epithelial cell migration / detection of muscle stretch / positive regulation of ubiquitin-dependent protein catabolic process / JUN kinase binding / signal complex assembly / positive regulation of macrophage proliferation / positive regulation of fibroblast migration / DCC mediated attractive signaling / Signal regulatory protein family interactions / growth hormone receptor signaling pathway / regulation of osteoblast differentiation / MET activates PTK2 signaling / regulation of focal adhesion assembly / establishment of cell polarity / positive regulation of wound healing / negative regulation of cell-cell adhesion / regulation of GTPase activity / positive regulation of macrophage chemotaxis / Fc-gamma receptor signaling pathway involved in phagocytosis / p130Cas linkage to MAPK signaling for integrins / positive regulation of epithelial cell migration / regulation of cytoskeleton organization / Apoptotic cleavage of cellular proteins / regulation of cell adhesion mediated by integrin / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of anoikis / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / ephrin receptor signaling pathway / positive regulation of protein kinase activity / regulation of cell adhesion / vascular endothelial growth factor receptor signaling pathway / positive regulation of epithelial to mesenchymal transition / heart morphogenesis / stress fiber / EPHB-mediated forward signaling / NCAM signaling for neurite out-growth / Integrin signaling / SH2 domain binding / transforming growth factor beta receptor signaling pathway / ciliary basal body / protein tyrosine phosphatase activity / molecular function activator activity / integrin-mediated signaling pathway / cell motility / FCGR3A-mediated phagocytosis / axon guidance / non-specific protein-tyrosine kinase / regulation of protein phosphorylation / non-membrane spanning protein tyrosine kinase activity / placenta development / epidermal growth factor receptor signaling pathway / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / cell migration / integrin binding / actin binding / regulation of cell population proliferation / cell cortex / regulation of cell shape / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / angiogenesis / protein autophosphorylation / dendritic spine / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cytoskeleton / positive regulation of cell migration / positive regulation of protein phosphorylation / intracellular membrane-bounded organelle / focal adhesion / centrosome / positive regulation of cell population proliferation / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain ...Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain / FERM/acyl-CoA-binding protein superfamily / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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-H82 / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsBader, G. / Zoephel, A.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions.
Authors: Popow, J. / Arnhof, H. / Bader, G. / Berger, H. / Ciulli, A. / Covini, D. / Dank, C. / Gmaschitz, T. / Greb, P. / Karolyi-Ozguer, J. / Koegl, M. / McConnell, D.B. / Pearson, M. / Rieger, M. ...Authors: Popow, J. / Arnhof, H. / Bader, G. / Berger, H. / Ciulli, A. / Covini, D. / Dank, C. / Gmaschitz, T. / Greb, P. / Karolyi-Ozguer, J. / Koegl, M. / McConnell, D.B. / Pearson, M. / Rieger, M. / Rinnenthal, J. / Roessler, V. / Schrenk, A. / Spina, M. / Steurer, S. / Trainor, N. / Traxler, E. / Wieshofer, C. / Zoephel, A. / Ettmayer, P.
History
DepositionNov 21, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 20, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 6, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Mar 27, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Jan 24, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8042
Polymers32,2471
Non-polymers5571
Water4,612256
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.050, 77.090, 82.710
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 Focal adhesion kinase 1 / FADK 1 / Focal adhesion kinase-related nonkinase / FRNK / Protein phosphatase 1 regulatory subunit ...FADK 1 / Focal adhesion kinase-related nonkinase / FRNK / Protein phosphatase 1 regulatory subunit 71 / PPP1R71 / Protein-tyrosine kinase 2 / p125FAK / pp125FAK


Mass: 32247.170 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK2, FAK, FAK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q05397, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-H82 / 3-methoxy-~{N}-(1-methylpiperidin-1-ium-4-yl)-4-[[4-[(3-oxidanylidene-1,2-dihydroinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide


Mass: 556.556 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H29F3N5O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / 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: 2.56 Å3/Da / Density % sol: 51.87 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 7%PEG1500, 100 mM SPG buffer, 5 mg/mL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.9102 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 20, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9102 Å / Relative weight: 1
ReflectionResolution: 1.99→20.77 Å / Num. obs: 40206 / % possible obs: 96.9 % / Redundancy: 3.32 % / Biso Wilson estimate: 30.1 Å2 / Rmerge F obs: 0.126 / Rmerge(I) obs: 0.064 / Rrim(I) all: 0.076 / Χ2: 0.982 / Net I/σ(I): 13.48 / Num. measured all: 133472 / Scaling rejects: 22
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRrim(I) all% possible all
1.99-2.113.3630.4062.8264810.48397.6
2.11-2.243.5720.284.2855480.32997.6
2.24-2.413.4670.1866.4955960.2297.6
2.41-2.623.3140.1249.1749990.14997.7
2.62-2.893.3510.08113.5544990.09797.3
2.89-3.283.2970.05319.3541560.06497.1
3.28-3.863.0070.03726.1534160.04694.7
3.86-4.953.070.02833.3528700.03495
4.95-7.793.0110.02733.2119480.03295.3
7.79-20.773.1170.02238.756930.02793.6

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.24data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ETM

2etm


Resolution: 1.99→20.77 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.916 / SU R Cruickshank DPI: 0.3 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.18 / SU Rfree Blow DPI: 0.154 / SU Rfree Cruickshank DPI: 0.147
RfactorNum. reflection% reflectionSelection details
Rfree0.222 1081 5 %RANDOM
Rwork0.183 ---
obs0.185 21624 99.7 %-
Displacement parametersBiso max: 121.83 Å2 / Biso mean: 33.75 Å2 / Biso min: 16.98 Å2
Baniso -1Baniso -2Baniso -3
1--0.2749 Å20 Å20 Å2
2---9.5598 Å20 Å2
3---9.8348 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.99→20.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2099 0 40 256 2395
Biso mean--27.07 43.26 -
Num. residues----261
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d955SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes698HARMONIC5
X-RAY DIFFRACTIONt_it4324HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion276SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4722SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4324HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg7822HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion3.26
X-RAY DIFFRACTIONt_other_torsion15.24
LS refinement shellResolution: 1.99→2 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2057 22 5.08 %
Rwork0.1966 411 -
all0.197 433 -
obs--99.77 %
Refinement TLS params.Method: refined / Origin x: 8.4983 Å / Origin y: 19.047 Å / Origin z: 20.0563 Å
111213212223313233
T-0.0502 Å2-0.0026 Å2-0.015 Å2--0.0864 Å20.0177 Å2---0.0414 Å2
L1.3674 °20.091 °2-0.5647 °2-0.27 °20.0847 °2--1.2728 °2
S0.0199 Å °0.0031 Å °-0.0074 Å °0.0006 Å °-0.0033 Å °-0.0079 Å °0.0868 Å °0.0511 Å °-0.0166 Å °
Refinement TLS groupSelection details: { A|* }

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