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- PDB-2zyb: Crystal structure of phenylimidazo pyrazin 2 bound to the kinase ... -

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Basic information

Entry
Database: PDB / ID: 2zyb
TitleCrystal structure of phenylimidazo pyrazin 2 bound to the kinase domain of human LCK, (auto-phosphorylated on TYR394)
ComponentsProto-oncogene tyrosine-protein kinase LCK
KeywordsTRANSFERASE / Tyrosine-protein kinase / ATP-binding / Phosphorylation / Signal transduction / Alternative splicing / Chromosomal rearrangement / Cytoplasm / Disease mutation / Host-virus interaction / Kinase / Lipoprotein / Membrane / Myristate / Nucleotide-binding / Palmitate / Phosphoprotein / Proto-oncogene / SH2 domain / SH3 domain / Cell membrane / Polymorphism
Function / homology
Function and homology information


regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway / CD28 co-stimulation / FLT3 signaling through SRC family kinases / intracellular zinc ion homeostasis / CD4 receptor binding / Nef Mediated CD4 Down-regulation / Nef and signal transduction / positive regulation of heterotypic cell-cell adhesion ...regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway / CD28 co-stimulation / FLT3 signaling through SRC family kinases / intracellular zinc ion homeostasis / CD4 receptor binding / Nef Mediated CD4 Down-regulation / Nef and signal transduction / positive regulation of heterotypic cell-cell adhesion / Interleukin-2 signaling / CD28 dependent Vav1 pathway / Regulation of KIT signaling / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / phospholipase activator activity / leukocyte migration / CD8 receptor binding / positive regulation of T cell receptor signaling pathway / pericentriolar material / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / PECAM1 interactions / CD28 dependent PI3K/Akt signaling / phospholipase binding / RHOH GTPase cycle / hemopoiesis / Generation of second messenger molecules / immunological synapse / T cell differentiation / PD-1 signaling / phosphatidylinositol 3-kinase binding / positive regulation of intrinsic apoptotic signaling pathway / T cell receptor binding / peptidyl-tyrosine autophosphorylation / release of sequestered calcium ion into cytosol / extrinsic component of cytoplasmic side of plasma membrane / GPVI-mediated activation cascade / T cell costimulation / phosphotyrosine residue binding / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / cell surface receptor protein tyrosine kinase signaling pathway / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Signaling by SCF-KIT / platelet activation / peptidyl-tyrosine phosphorylation / activation of cysteine-type endopeptidase activity involved in apoptotic process / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of T cell activation / Downstream TCR signaling / PIP3 activates AKT signaling / DAP12 signaling / T cell receptor signaling pathway / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein phosphatase binding / protein tyrosine kinase activity / intracellular signal transduction / response to xenobiotic stimulus / membrane raft / protein phosphorylation / signaling receptor binding / innate immune response / protein kinase binding / extracellular exosome / ATP binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Lck, SH3 domain / Tyrosine-protein kinase Lck, 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 ...Lck, SH3 domain / Tyrosine-protein kinase Lck, 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-KSL / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsTsuji, E.
CitationJournal: Bioorg.Med.Chem. / Year: 2008
Title: The importance of CH/pi hydrogen bonds in rational drug design: An ab initio fragment molecular orbital study to leukocyte-specific protein tyrosine (LCK) kinase
Authors: Ozawa, T. / Tsuji, E. / Ozawa, M. / Handa, C. / Mukaiyama, H. / Nishimura, T. / Kobayashi, S. / Okazaki, K.
History
DepositionJan 19, 2009Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4763
Polymers33,0661
Non-polymers4102
Water3,621201
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.150, 73.973, 92.857
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 Proto-oncogene tyrosine-protein kinase LCK / Lymphocyte cell-specific protein-tyrosine kinase / p56-LCK / LSK / T cell-specific protein-tyrosine kinase


Mass: 33065.602 Da / Num. of mol.: 1 / Fragment: UNP residues 225-509
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LCK / Plasmid: PET-19B / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P06239, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-KSL / N-(2,6-dimethylphenyl)-5-phenylimidazo[1,5-a]pyrazin-8-amine


Mass: 314.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18N4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.19 Å3/Da / Density % sol: 43.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2M (NH4)2SO4, 0.1M Sodium cacodylate, 30% PEG8000, pH6.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32B2 / Wavelength: 1 Å
DetectorType: RIGAKU JUPITER 210 / Detector: CCD / Date: Jan 1, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→28.51 Å / Num. all: 9817 / Num. obs: 9965 / % possible obs: 98.5 % / Redundancy: 3.3 % / Biso Wilson estimate: 26.7 Å2 / Rmerge(I) obs: 0.101 / Rsym value: 0.12 / Net I/σ(I): 11.8
Reflection shellResolution: 2.55→2.69 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.211 / Mean I/σ(I) obs: 5.9 / Num. unique all: 1372 / Rsym value: 0.248 / % possible all: 96.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
BSSAT BL32B2data collection
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3LCK

3lck


Resolution: 2.55→15 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.818 / SU B: 11.722 / SU ML: 0.252 / Cross valid method: THROUGHOUT / ESU R Free: 0.408 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29127 968 9.9 %RANDOM
Rwork0.17145 ---
obs0.18336 8763 98.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 8.431 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20 Å20 Å2
2--0.48 Å20 Å2
3----0.52 Å2
Refinement stepCycle: LAST / Resolution: 2.55→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2209 0 29 201 2439
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0222295
X-RAY DIFFRACTIONr_angle_refined_deg1.6621.9833117
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.8255270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.14723.796108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.39515394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4331517
X-RAY DIFFRACTIONr_chiral_restr0.1380.2332
X-RAY DIFFRACTIONr_gen_planes_refined0.0280.021751
X-RAY DIFFRACTIONr_nbd_refined0.2750.21134
X-RAY DIFFRACTIONr_nbtor_refined0.3350.21534
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2290.2138
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3020.258
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.5490.226
X-RAY DIFFRACTIONr_mcbond_it2.3151.51407
X-RAY DIFFRACTIONr_mcangle_it3.32422192
X-RAY DIFFRACTIONr_scbond_it4.96931064
X-RAY DIFFRACTIONr_scangle_it6.6024.5925
LS refinement shellResolution: 2.55→2.614 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 64 -
Rwork0.256 610 -
obs--95.6 %

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