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- PDB-5da3: Crystal structure of PTK6 Kinase domain with inhibitor -

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Basic information

Entry
Database: PDB / ID: 5da3
TitleCrystal structure of PTK6 Kinase domain with inhibitor
ComponentsProtein-tyrosine kinase 6
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PTK6 / BRK / Complex / Inhibitor / Kinase / Transferase / Imidazo pyrazin / 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 / positive regulation of cell cycle / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / cellular response to retinoic acid / positive regulation of tyrosine phosphorylation of STAT protein / ruffle / cell surface receptor protein tyrosine kinase signaling pathway / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / positive regulation of DNA replication / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Cytoprotection by HMOX1 / SCF(Skp2)-mediated degradation of p27/p21 / positive regulation of neuron projection development / Cyclin D associated events in G1 / cell migration / protein tyrosine kinase activity / protein autophosphorylation / cell differentiation / nuclear body / protein phosphorylation / innate immune response / signaling receptor binding / nucleoplasm / ATP binding / identical protein binding / nucleus / plasma membrane / cytoplasm / cytosol
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
Chem-58V / Protein-tyrosine kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsThakur, M.K. / Birudukota, S. / Swaminathan, S. / Battula, S.K. / Vadivelu, S. / Tyagi, R. / Gosu, R.
CitationJournal: Biochem. Biophys. Res. Commun. / Year: 2017
Title: Co-crystal structures of PTK6: With Dasatinib at 2.24 angstrom , with novel imidazo[1,2-a]pyrazin-8-amine derivative inhibitor at 1.70 angstrom resolution
Authors: Thakur, M.K. / Birudukota, S. / Swaminathan, S. / Battula, S.K. / Vadivelu, S. / Tyagi, R. / Gosu, R.
History
DepositionAug 19, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Aug 24, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2017Group: Database references
Revision 1.2Jan 25, 2017Group: Database references
Revision 1.3Nov 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
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)31,2364
Polymers30,5881
Non-polymers6483
Water3,459192
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area590 Å2
ΔGint-2 kcal/mol
Surface area11870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.372, 48.403, 71.924
Angle α, β, γ (deg.)90.000, 105.140, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 30588.330 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP residues 185-446 / Mutation: C433T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK6 / Plasmid: pFastBac1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13882, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-58V / (2-chloro-4-{[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino}phenyl)(morpholin-4-yl)methanone


Mass: 463.919 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22ClN7O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 2.48 Å3/Da / Density % sol: 50.45 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: 0.2 M tri-Lithium citrate, 20% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54179 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jun 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54179 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 33176 / % possible obs: 91.7 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.027 / Rrim(I) all: 0.073 / Χ2: 1.053 / Net I/av σ(I): 28.458 / Net I/σ(I): 15.5 / Num. measured all: 207286
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.7-1.762.80.39620610.8160.2380.4661.07263.1
1.76-1.834.90.35829350.9010.170.3981.07289.2
1.83-1.916.80.26430570.9420.1080.2861.07492.6
1.91-2.027.40.18230790.9850.0710.1951.04793.3
2.02-2.147.50.12831120.9920.050.1371.06894.3
2.14-2.317.50.131720.9940.0390.1071.02695.1
2.31-2.547.50.08431480.9960.0330.091.04695.8
2.54-2.917.50.06932110.9960.0270.0741.08296.7
2.91-3.667.50.05732780.9970.0220.0611.04997.8
3.66-507.30.05433720.9970.0210.0581.0298.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
REFMAC5.2.0005refinement
PDB_EXTRACT3.15data extraction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5D7V

5d7v


Resolution: 1.7→50 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.945 / SU B: 2.324 / SU ML: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.126 / ESU R Free: 0.12 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2302 1548 5.1 %RANDOM
Rwork0.1974 ---
obs0.1991 28876 91.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 48.45 Å2 / Biso mean: 22.476 Å2 / Biso min: 11.14 Å2
Baniso -1Baniso -2Baniso -3
1--0.85 Å20 Å20.36 Å2
2--0.4 Å20 Å2
3---0.64 Å2
Refinement stepCycle: final / Resolution: 1.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2126 0 52 192 2370
Biso mean--19.7 30.31 -
Num. residues----264
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0212336
X-RAY DIFFRACTIONr_angle_refined_deg1.2741.9913182
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3185289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.51923.056108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.48615411
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1241519
X-RAY DIFFRACTIONr_chiral_restr0.0810.2338
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021831
X-RAY DIFFRACTIONr_nbd_refined0.2180.21233
X-RAY DIFFRACTIONr_nbtor_refined0.3050.21594
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1150.2184
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1970.242
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1970.214
X-RAY DIFFRACTIONr_mcbond_it0.5191.51404
X-RAY DIFFRACTIONr_mcangle_it0.86122213
X-RAY DIFFRACTIONr_scbond_it1.46431063
X-RAY DIFFRACTIONr_scangle_it2.2284.5951
LS refinement shellResolution: 1.701→1.745 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.511 75 -
Rwork0.443 1336 -
all-1411 -
obs--58.52 %

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