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- PDB-6cz3: Structure of the PTK6 kinase domain bound to a type I inhibitor (... -

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Basic information

Entry
Database: PDB / ID: 6cz3
TitleStructure of the PTK6 kinase domain bound to a type I inhibitor (3-fluoro-4-{[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino}phenyl)(morpholin-4-yl)methanone
ComponentsProtein-tyrosine kinase 6Tyrosine kinase
KeywordsTransferase/Transferase Inhibitor / Protein kinase / PTK6 / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


PTK6 Activates STAT3 / negative regulation of protein tyrosine kinase activity / PTK6 Regulates Proteins Involved in RNA Processing / intestinal epithelial cell differentiation / ERBB2 signaling pathway / negative regulation of growth / PTK6 Expression / tyrosine phosphorylation of STAT protein / positive regulation of epidermal growth factor receptor signaling pathway / PTK6 promotes HIF1A stabilization ...PTK6 Activates STAT3 / negative regulation of protein tyrosine kinase activity / PTK6 Regulates Proteins Involved in RNA Processing / intestinal epithelial cell differentiation / ERBB2 signaling pathway / negative regulation of growth / PTK6 Expression / tyrosine phosphorylation of STAT protein / positive regulation of epidermal growth factor receptor signaling pathway / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / PTK6 Down-Regulation / PTK6 Regulates Cell Cycle / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / positive regulation of cell cycle / cellular response to retinoic acid / positive regulation of tyrosine phosphorylation of STAT protein / ruffle / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of DNA replication / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / positive regulation of neuron projection development / Cytoprotection by HMOX1 / SCF(Skp2)-mediated degradation of p27/p21 / cell surface receptor protein tyrosine kinase signaling pathway / Cyclin D associated events in G1 / cell migration / protein tyrosine kinase activity / protein autophosphorylation / cell differentiation / nuclear body / signaling receptor binding / protein phosphorylation / innate immune response / nucleoplasm / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PTK6, SH2 domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. ...PTK6, SH2 domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / 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, 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
ACETATE ION / Chem-FLJ / : / Protein-tyrosine kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsGajiwala, K.S. / Johnson, E. / Cronin, C.N.
CitationJournal: PLoS ONE / Year: 2018
Title: Small molecule inhibitors reveal PTK6 kinase is not an oncogenic driver in breast cancers.
Authors: Qiu, L. / Levine, K. / Gajiwala, K.S. / Cronin, C.N. / Nagata, A. / Johnson, E. / Kraus, M. / Tatlock, J. / Kania, R. / Foley, T. / Sun, S.
History
DepositionApr 7, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 20, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Protein-tyrosine kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,16211
Polymers30,2491
Non-polymers91310
Water2,018112
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)107.910, 107.910, 84.794
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Protein-tyrosine kinase 6 / Tyrosine kinase / Breast tumor kinase / Tyrosine-protein kinase BRK


Mass: 30248.904 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK6, BRK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13882, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-FLJ / (3-fluoro-4-{[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino}phenyl)(morpholin-4-yl)methanone


Mass: 421.428 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20FN7O2
#3: Chemical
ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 112 / 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: 3.14 Å3/Da / Density % sol: 60.84 %
Crystal growTemperature: 288 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 3.4 M Potassium acetate, 0.1 M bicine, pH 7.5, 13oC
PH range: 7.5 - 8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jan 26, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→38.61 Å / Num. obs: 34192 / % possible obs: 99.9 % / Redundancy: 5.8 % / Biso Wilson estimate: 28.9 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.039 / Rpim(I) all: 0.018 / Rrim(I) all: 0.043 / Net I/σ(I): 24.3
Reflection shellResolution: 1.8→2.01 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.468 / Mean I/σ(I) obs: 3.7 / CC1/2: 0.924 / Rpim(I) all: 0.215 / Rrim(I) all: 0.515 / % possible all: 100

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Processing

Software
NameVersionClassification
CNX2005refinement
XDSdata reduction
Aimlessdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→38.61 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 1855400.62 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.213 1689 5 %RANDOM
Rwork0.196 ---
obs0.197 34083 99.9 %-
Solvent computationBsol: 46.4784 Å2 / ksol: 0.395202 e/Å3
Displacement parametersBiso mean: 37.5 Å2
Baniso -1Baniso -2Baniso -3
1-3.33 Å23.36 Å20 Å2
2--3.33 Å20 Å2
3----6.65 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.26 Å0.22 Å
Refinement stepCycle: 1 / Resolution: 1.8→38.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2188 0 61 112 2361
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.411.5
X-RAY DIFFRACTIONc_mcangle_it2.182
X-RAY DIFFRACTIONc_scbond_it2.012
X-RAY DIFFRACTIONc_scangle_it3.182.5
LS refinement shellResolution: 1.8→1.91 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.321 271 4.8 %
Rwork0.296 5399 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1ACCELRYS_CNX:libraries/toppar/protein_rep.paraACCELRYS_CNX:libraries/toppar/protein.top
X-RAY DIFFRACTION2ACCELRYS_CNX:libraries/toppar/dna-rna_rep.paraACCELRYS_CNX:libraries/toppar/dna-rna.top
X-RAY DIFFRACTION3ACCELRYS_CNX:libraries/toppar/water_rep.paramACCELRYS_CNX:libraries/toppar/water.top
X-RAY DIFFRACTION4ACCELRYS_CNX:libraries/toppar/ion.paramACCELRYS_CNX:libraries/toppar/ion.top
X-RAY DIFFRACTION5lig-edited.parlig-edited.top

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