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- PDB-6cz4: Structure of the PTK6 kinase domain bound to a type II inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 6cz4
TitleStructure of the PTK6 kinase domain bound to a type II inhibitor 2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-carboxamide
ComponentsProtein-tyrosine kinase 6
KeywordsTransferase/Transferase Inhibitor / Protein kinase / PTK6 / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


negative regulation of protein tyrosine kinase activity / PTK6 Activates STAT3 / 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 ...negative regulation of protein tyrosine kinase activity / PTK6 Activates STAT3 / 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 Down-Regulation / ERBB2 Activates PTK6 Signaling / PTK6 Regulates Cell Cycle / positive regulation of cell cycle / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to retinoic acid / ruffle / 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 / positive regulation of receptor signaling pathway via JAK-STAT / 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 / 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 ...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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-FKY / Protein-tyrosine kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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 1.1Oct 3, 2018Group: Data collection / Refinement description / Category: pdbx_refine / pdbx_xplor_file / refine
Item: _pdbx_refine.pdbx_refine_id / _pdbx_xplor_file.pdbx_refine_id
Revision 1.2Mar 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)30,7702
Polymers30,2491
Non-polymers5211
Water3,243180
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.914, 54.873, 134.629
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Protein-tyrosine kinase 6 / 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-FKY / 2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-carboxamide


Mass: 521.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23F4N5O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.31 Å3/Da / Density % sol: 46.87 %
Crystal growTemperature: 286 K / Method: vapor diffusion, sitting drop
Details: 1.25 M Sodium dihydrogen phosphate, 0.89 M di-Potassium hydrogen phosphate, 0.2 M Lithium sulfate, 0.1 M CHES, pH 9.8, 13o C

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 19, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.48→50.82 Å / Num. obs: 46820 / % possible obs: 97.9 % / Redundancy: 5.9 % / Biso Wilson estimate: 24.8 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.016 / Rrim(I) all: 0.041 / Net I/σ(I): 22.9
Reflection shellResolution: 1.48→1.56 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.418 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 5842 / CC1/2: 0.903 / Rpim(I) all: 0.239 / Rrim(I) all: 0.485 / % possible all: 86.8

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Processing

Software
NameVersionClassification
CNX2005refinement
XDSdata reduction
Aimlessdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→50.82 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 1090310.76 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.209 2202 4.9 %RANDOM
Rwork0.203 ---
obs0.203 45221 98.4 %-
Solvent computationBsol: 43.8964 Å2 / ksol: 0.374408 e/Å3
Displacement parametersBiso mean: 28.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.7 Å20 Å20 Å2
2--6.45 Å20 Å2
3----5.75 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.19 Å0.18 Å
Luzzati d res low-5 Å
Luzzati sigma a0.17 Å0.15 Å
Refinement stepCycle: 1 / Resolution: 1.5→50.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2109 0 37 180 2326
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
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_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.61
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.321.5
X-RAY DIFFRACTIONc_mcangle_it2.142
X-RAY DIFFRACTIONc_scbond_it2.162
X-RAY DIFFRACTIONc_scangle_it3.322.5
LS refinement shellResolution: 1.5→1.59 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.294 326 4.8 %
Rwork0.273 6505 -
obs--90.6 %
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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