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- PDB-5h2u: Crystal structure of PTK6 Kinase Domain complexed with Dasatinib -

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Basic information

Entry
Database: PDB / ID: 5h2u
TitleCrystal structure of PTK6 Kinase Domain complexed with Dasatinib
ComponentsProtein-tyrosine kinase 6Tyrosine kinase
KeywordsTRANSFERASE / Kinase / BRK / PTK6 / Dasatinib
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 / Cytoprotection by HMOX1 / SCF(Skp2)-mediated degradation of p27/p21 / positive regulation of neuron projection development / 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 / protein phosphorylation / signaling receptor binding / 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
Chem-1N1 / Protein-tyrosine kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
AuthorsThakur, M.K. / Birudukota, S. / Swaminathan, 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
DepositionOct 18, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 4, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2017Group: Database references
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
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
B: Protein-tyrosine kinase 6
C: Protein-tyrosine kinase 6
D: Protein-tyrosine kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,51620
Polymers123,4584
Non-polymers3,05716
Water9,026501
1
A: Protein-tyrosine kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6295
Polymers30,8651
Non-polymers7644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-3 kcal/mol
Surface area12610 Å2
MethodPISA
2
B: Protein-tyrosine kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6295
Polymers30,8651
Non-polymers7644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area830 Å2
ΔGint-3 kcal/mol
Surface area12170 Å2
MethodPISA
3
C: Protein-tyrosine kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6295
Polymers30,8651
Non-polymers7644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area940 Å2
ΔGint-3 kcal/mol
Surface area12330 Å2
MethodPISA
4
D: Protein-tyrosine kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6295
Polymers30,8651
Non-polymers7644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area830 Å2
ΔGint-3 kcal/mol
Surface area12150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.881, 77.018, 87.413
Angle α, β, γ (deg.)81.360, 75.760, 74.920
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 30864.621 Da / Num. of mol.: 4 / 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-1N1 / N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE / Dasatinib / Dasatinib


Mass: 488.006 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H26ClN7O2S / Comment: medication*YM
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 501 / 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: 2.53 Å3/Da / Density % sol: 51.48 %
Crystal growTemperature: 298 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: 1.54789 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Oct 28, 2015 / Details: VariMax HR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54789 Å / Relative weight: 1
ReflectionResolution: 2.24→84.52 Å / Num. obs: 58073 / % possible obs: 94.7 % / Redundancy: 2.4 % / Rmerge(I) obs: 0.099 / Net I/σ(I): 9.3
Reflection shellResolution: 2.24→2.32 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.487 / Mean I/σ(I) obs: 1.5 / % possible all: 83.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
MOLREPphasing
HKLdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5D7V

5d7v


Resolution: 2.24→84.52 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.894 / SU B: 7.965 / SU ML: 0.204 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.393 / ESU R Free: 0.258 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2601 2789 5.1 %RANDOM
Rwork0.2055 ---
obs0.2083 52220 94.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 58.73 Å2 / Biso mean: 33.687 Å2 / Biso min: 20.32 Å2
Baniso -1Baniso -2Baniso -3
1-0.85 Å2-0.52 Å20.96 Å2
2--0.23 Å2-0.05 Å2
3----1.26 Å2
Refinement stepCycle: final / Resolution: 2.24→84.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8541 0 236 501 9278
Biso mean--37.68 37.78 -
Num. residues----1059
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0219307
X-RAY DIFFRACTIONr_angle_refined_deg1.311.98312627
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.84451136
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.87122.86437
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.93151610
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8961579
X-RAY DIFFRACTIONr_chiral_restr0.0860.21324
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027279
X-RAY DIFFRACTIONr_nbd_refined0.2080.24521
X-RAY DIFFRACTIONr_nbtor_refined0.2990.26188
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1710.2580
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2040.2118
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1830.225
X-RAY DIFFRACTIONr_mcbond_it0.491.55639
X-RAY DIFFRACTIONr_mcangle_it0.83428813
X-RAY DIFFRACTIONr_scbond_it1.21234241
X-RAY DIFFRACTIONr_scangle_it1.9134.53769
LS refinement shellResolution: 2.241→2.299 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 148 -
Rwork0.268 3222 -
all-3370 -
obs--78.39 %

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