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- PDB-9byj: Crystal Structure of Hck in complex with the Src-family kinase in... -

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Basic information

Entry
Database: PDB / ID: 9byj
TitleCrystal Structure of Hck in complex with the Src-family kinase inhibitor A-419259
ComponentsTyrosine-protein kinase HCK
KeywordsTRANSFERASE / Src Family kinase / Inhibitor / Transferase Inhibitor / Tyrosine kinase
Function / homology
Function and homology information


leukocyte degranulation / innate immune response-activating signaling pathway / respiratory burst after phagocytosis / leukocyte migration involved in immune response / regulation of podosome assembly / FLT3 signaling through SRC family kinases / regulation of phagocytosis / Nef and signal transduction / regulation of DNA-binding transcription factor activity / positive regulation of actin filament polymerization ...leukocyte degranulation / innate immune response-activating signaling pathway / respiratory burst after phagocytosis / leukocyte migration involved in immune response / regulation of podosome assembly / FLT3 signaling through SRC family kinases / regulation of phagocytosis / Nef and signal transduction / regulation of DNA-binding transcription factor activity / positive regulation of actin filament polymerization / Fc-gamma receptor signaling pathway involved in phagocytosis / mesoderm development / FCGR activation / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / transport vesicle / phosphotyrosine residue binding / FCGR3A-mediated IL10 synthesis / lipopolysaccharide-mediated signaling pathway / cell surface receptor protein tyrosine kinase signaling pathway / integrin-mediated signaling pathway / cell projection / non-membrane spanning protein tyrosine kinase activity / regulation of actin cytoskeleton organization / FCGR3A-mediated phagocytosis / Regulation of signaling by CBL / non-specific protein-tyrosine kinase / negative regulation of inflammatory response to antigenic stimulus / cytokine-mediated signaling pathway / Inactivation of CSF3 (G-CSF) signaling / peptidyl-tyrosine phosphorylation / caveola / cytoplasmic side of plasma membrane / Signaling by CSF1 (M-CSF) in myeloid cells / regulation of cell shape / protein autophosphorylation / regulation of inflammatory response / protein tyrosine kinase activity / cell differentiation / cytoskeleton / lysosome / cell adhesion / intracellular signal transduction / protein phosphorylation / inflammatory response / signaling receptor binding / focal adhesion / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / lipid binding / negative regulation of apoptotic process / Golgi apparatus / ATP binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase HCK, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Src homology 3 domains / SH3-like domain superfamily ...Tyrosine-protein kinase HCK, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Src homology 3 domains / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
THIOCYANATE ION / Chem-VSE / Tyrosine-protein kinase HCK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsSelzer, A.M. / Alvarado, J.J. / Smithgall, T.E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA233576 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)F31 CA265294 United States
CitationJournal: Biochemistry / Year: 2024
Title: Cocrystallization of the Src-Family Kinase Hck with the ATP-Site Inhibitor A-419259 Stabilizes an Extended Activation Loop Conformation.
Authors: Selzer, A.M. / Alvarado, J.J. / Smithgall, T.E.
History
DepositionMay 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,16925
Polymers52,2861
Non-polymers1,88324
Water3,945219
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.346, 85.025, 128.798
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Tyrosine-protein kinase HCK / Hematopoietic cell kinase / Hemopoietic cell kinase / p59-HCK/p60-HCK / p59Hck / p61Hck


Mass: 52286.492 Da / Num. of mol.: 1 / Mutation: Q523E,Q524E,Q525I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCK / Plasmid: Pet28a Hck YEEI / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star
References: UniProt: P08631, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 243 molecules

#2: Chemical ChemComp-VSE / 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 482.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H34N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: CNS
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 219 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.32 Å3/Da / Density % sol: 47.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 10 mM Tris-HCl, pH 8.3, 75 mM NaCl, 5% glycerol, 2 mM TCEP, 0.1 M sodium thiocyanate, 10% w/v PEG 3350, 0.095 mM 7-[trans-4-(4-Methyl-1-piperazinyl)cyclohexyl]-5-(4-phenoxyphenyl)-7H- ...Details: 10 mM Tris-HCl, pH 8.3, 75 mM NaCl, 5% glycerol, 2 mM TCEP, 0.1 M sodium thiocyanate, 10% w/v PEG 3350, 0.095 mM 7-[trans-4-(4-Methyl-1-piperazinyl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-Pyrrolo[2,3-d]pyrimidin-4-amine, 0.5 mM N~2~-{[2-(2,4-difluorophenoxy)pyridin-3-yl]methyl}-N~4~-isopropylpyrimidine-2,4-diamine,1 % DMSO
Temp details: room temperature

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03317 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 19, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03317 Å / Relative weight: 1
ReflectionResolution: 1.8→42.5125 Å / Num. obs: 44990 / % possible obs: 99.95 % / Redundancy: 7.1 % / Biso Wilson estimate: 33.27 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.148 / Rrim(I) all: 0.16 / Net I/σ(I): 8.5
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 6.97 % / Rmerge(I) obs: 2.898 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 4379 / CC1/2: 0.301 / Rrim(I) all: 3.135 / % possible all: 99.64

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Blu-Icedata collection
XDSdata reduction
PHASERphasing
Cootmodel building
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→42.51 Å / SU ML: 0.278 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.1326
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2192 3764 4.46 %
Rwork0.1994 80673 -
obs0.2003 42703 99.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.67 Å2
Refinement stepCycle: LAST / Resolution: 1.8→42.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3580 0 113 219 3912
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01493802
X-RAY DIFFRACTIONf_angle_d1.60095118
X-RAY DIFFRACTIONf_chiral_restr0.0967539
X-RAY DIFFRACTIONf_plane_restr0.0301648
X-RAY DIFFRACTIONf_dihedral_angle_d16.73161433
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.820.36611250.38392588X-RAY DIFFRACTION88.08
1.82-1.850.39921290.37142865X-RAY DIFFRACTION94.57
1.85-1.870.35141370.35362987X-RAY DIFFRACTION98.02
1.87-1.90.37221360.33422953X-RAY DIFFRACTION98.72
1.9-1.930.34071420.3262980X-RAY DIFFRACTION99.17
1.93-1.960.31751420.31643028X-RAY DIFFRACTION99.72
1.96-1.990.28921420.29863016X-RAY DIFFRACTION99.91
1.99-2.020.26141390.28783007X-RAY DIFFRACTION99.94
2.02-2.060.25671400.28573044X-RAY DIFFRACTION99.94
2.06-2.10.3161320.27732960X-RAY DIFFRACTION99.9
2.1-2.140.31451420.27993036X-RAY DIFFRACTION99.87
2.14-2.190.33081390.26213022X-RAY DIFFRACTION99.84
2.19-2.240.23741360.23883020X-RAY DIFFRACTION99.87
2.24-2.30.2481420.24093033X-RAY DIFFRACTION100
2.3-2.360.25841410.2232965X-RAY DIFFRACTION100
2.36-2.430.22751440.21543071X-RAY DIFFRACTION99.94
2.43-2.510.24511380.20453011X-RAY DIFFRACTION100
2.51-2.60.23081360.21682982X-RAY DIFFRACTION100
2.6-2.70.25921410.20783031X-RAY DIFFRACTION99.97
2.7-2.820.21331440.20813002X-RAY DIFFRACTION100
2.82-2.970.231440.19843020X-RAY DIFFRACTION99.97
2.97-3.160.18421380.18763021X-RAY DIFFRACTION99.56
3.16-3.40.221460.16952999X-RAY DIFFRACTION99.9
3.4-3.740.19231430.16182994X-RAY DIFFRACTION100
3.74-4.280.17911430.14033032X-RAY DIFFRACTION99.94
4.28-5.390.15841400.15063000X-RAY DIFFRACTION99.71
5.4-42.510.17411430.17583006X-RAY DIFFRACTION99.72

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