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- PDB-2hk5: Hck Kinase in Complex with Lck targetted Inhibitor PG-1009247 -

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Basic information

Entry
Database: PDB / ID: 2hk5
TitleHck Kinase in Complex with Lck targetted Inhibitor PG-1009247
ComponentsTyrosine-protein kinase HCK
KeywordsTRANSFERASE / Hck / Src-family / Kinase Domain
Function / homology
Function and homology information


leukocyte degranulation / respiratory burst after phagocytosis / innate immune response-activating signaling pathway / leukocyte migration involved in immune response / regulation of podosome assembly / regulation of phagocytosis / FLT3 signaling through SRC family kinases / Nef and signal transduction / regulation of DNA-binding transcription factor activity / positive regulation of actin filament polymerization ...leukocyte degranulation / respiratory burst after phagocytosis / innate immune response-activating signaling pathway / leukocyte migration involved in immune response / regulation of podosome assembly / regulation of phagocytosis / FLT3 signaling through SRC family kinases / 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 / localization / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / lipopolysaccharide-mediated signaling pathway / transport vesicle / negative regulation of inflammatory response to antigenic stimulus / extrinsic component of cytoplasmic side of plasma membrane / cell surface receptor protein tyrosine kinase signaling pathway / phosphotyrosine residue binding / FCGR3A-mediated IL10 synthesis / caveola / cell projection / integrin-mediated signaling pathway / Regulation of signaling by CBL / regulation of actin cytoskeleton organization / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / Signaling by CSF1 (M-CSF) in myeloid cells / regulation of cell shape / regulation of inflammatory response / protein tyrosine kinase activity / protein autophosphorylation / cell differentiation / lysosome / cytoskeleton / cell adhesion / intracellular signal transduction / inflammatory response / protein phosphorylation / intracellular membrane-bounded organelle / innate immune response / focal adhesion / signaling receptor binding / lipid binding / positive regulation of cell population proliferation / 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 / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. ...Tyrosine-protein kinase HCK, 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-1BM / Tyrosine-protein kinase HCK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsWalter, R.L. / Mekel, M.J. / Evdokimov, A.G. / Pokross, M.E. / Sabat, M.P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck).
Authors: Sabat, M. / VanRens, J.C. / Laufersweiler, M.J. / Brugel, T.A. / Maier, J. / Golebiowski, A. / De, B. / Easwaran, V. / Hsieh, L.C. / Walter, R.L. / Mekel, M.J. / Evdokimov, A. / Janusz, M.J.
History
DepositionJul 3, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 5, 2006Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 15, 2015Group: Database references
Revision 1.4Oct 18, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.5Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)31,4022
Polymers30,9711
Non-polymers4321
Water4,161231
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)96.977, 96.977, 69.998
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65

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Components

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


Mass: 30970.830 Da / Num. of mol.: 1 / Fragment: Kinase Domian (Residues 246-513)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCK / Production host: Escherichia coli (E. coli)
References: UniProt: P08631, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-1BM / 3-{[2-(1H-BENZIMIDAZOL-1-YL)-6-{[2-(DIETHYLAMINO)ETHYL]AMINO}PYRIMIDIN-4-YL]AMINO}-4-METHYLPHENOL


Mass: 431.533 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29N7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 3.07 Å3/Da / Density % sol: 59.89 %
Crystal growTemperature: 288 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.5-3.0M Ammonium Sulfate or Sodium Formate or 18 - 28% PEG 10K + 0.1M HEPES or Tris, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 288K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 1, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionRedundancy: 3.8 % / Av σ(I) over netI: 4.5 / Number: 89396 / Rmerge(I) obs: 0.177 / Χ2: 1.33 / D res high: 2 Å / D res low: 50 Å / Num. obs: 23300 / % possible obs: 91.5
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
4.585095.210.0832.1364.4
3.634.5897.810.081.4864.5
3.173.6398.210.1361.6324.5
2.883.1798.610.2291.3944.4
2.682.889910.3471.184.4
2.522.6899.210.4491.1054.3
2.392.5298.210.5071.0753.9
2.292.3995.210.5461.1043.5
2.22.2991.210.5731.0743.1
2.132.283.110.5780.9742.9
2.062.1374.210.6490.932.7
22.0666.910.7540.872.4
ReflectionResolution: 2→50 Å / Num. obs: 23300 / % possible obs: 91.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 3.8 % / Rmerge(I) obs: 0.177 / Χ2: 1.33 / Net I/σ(I): 4.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2-2.062.40.75414090.87166.9
2.06-2.132.70.64915610.93174.2
2.13-2.22.90.57817490.974183.1
2.2-2.293.10.57319261.074191.2
2.29-2.393.50.54620141.104195.2
2.39-2.523.90.50720661.075198.2
2.52-2.684.30.44921081.105199.2
2.68-2.884.40.34721001.18199
2.88-3.174.40.22921011.394198.6
3.17-3.634.50.13620861.632198.2
3.63-4.584.50.0820911.486197.8
4.58-504.40.08320892.136195.2

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Phasing

Phasing MRRfactor: 0.404 / Cor.coef. Fo:Fc: 0.592 / Cor.coef. Io to Ic: 0.289
Highest resolutionLowest resolution
Rotation3 Å84.515 Å
Translation3 Å84.515 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement
PDB_EXTRACT2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Hck internal

Resolution: 2→39.9 Å / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.2502 112 5% random
Rwork0.1981 --
all0.2014 25438 -
obs0.2 22107 -
Displacement parametersBiso mean: 25.187 Å2
Refinement stepCycle: LAST / Resolution: 2→39.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2166 0 32 231 2429
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONp_bond_d0.015
X-RAY DIFFRACTIONp_angle_d1.483
X-RAY DIFFRACTIONp_chiral_restr0.084

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