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- PDB-3ac8: Crystal structure of pyrazolo pyrimidine derivative bound to the ... -

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Basic information

Entry
Database: PDB / ID: 3ac8
TitleCrystal structure of pyrazolo pyrimidine derivative 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 / KINASE / SH2 DOMAIN / SH3 DOMAIN
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 and signal transduction / Nef Mediated CD4 Down-regulation / Interleukin-2 signaling ...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 and signal transduction / Nef Mediated CD4 Down-regulation / Interleukin-2 signaling / CD28 dependent Vav1 pathway / positive regulation of heterotypic cell-cell adhesion / protein serine/threonine phosphatase activity / Regulation of KIT signaling / CTLA4 inhibitory signaling / phospholipase activator activity / positive regulation of T cell receptor signaling pathway / leukocyte migration / pericentriolar material / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / phospholipase binding / PECAM1 interactions / CD28 dependent PI3K/Akt signaling / RHOH GTPase cycle / hemopoiesis / Generation of second messenger molecules / immunological synapse / T cell differentiation / PD-1 signaling / CD8 receptor binding / phosphatidylinositol 3-kinase binding / positive regulation of intrinsic apoptotic signaling pathway / peptidyl-tyrosine autophosphorylation / release of sequestered calcium ion into cytosol / GPVI-mediated activation cascade / T cell costimulation / extrinsic component of cytoplasmic side of plasma membrane / SH2 domain binding / phosphotyrosine residue binding / T cell receptor binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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 / ATPase binding / T cell receptor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein phosphatase binding / protein tyrosine kinase activity / intracellular signal transduction / response to xenobiotic stimulus / membrane raft / signaling receptor binding / protein phosphorylation / 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 / Src homology 3 domains / SH2 domain / 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 / Src homology 3 domains / SH2 domain / 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-KSK / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsTsuji, E.
CitationJournal: To be Published
Title: Ab initio fragment molecular orbital study of ligand binding to leukocyte-specific protein tyrosine (LCK) kinase
Authors: Ozawa, M. / Ozawa, T. / Tsuji, E. / Okazaki, K. / Takeda, K.
History
DepositionDec 29, 2009Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 30, 2010Provider: 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)33,6974
Polymers33,0661
Non-polymers6323
Water3,891216
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.261, 73.766, 93.010
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 KINASE / LCK / Lymphocyte cell-specific protein-tyrosine kinase / p56-LCK / LSK / T cell- ...LYMPHOCYTE 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 / 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.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-KSK / 7-[(2-amino-2-methylpropyl)amino]-5-cyclopropyl-2-[(3,5-dimethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 439.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29N7O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 216 / 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: 43.89 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2M (NH4)2SO4, 0.1M SODIUM CACODYLATE, 30% PEG 8000, 0.2% MPD, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32B2 / Wavelength: 1.5418 Å
DetectorType: RIGAKU JUPITER 210 / Detector: CCD / Date: Dec 17, 2002
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→28.58 Å / Num. all: 13144 / Num. obs: 13182 / % possible obs: 98 % / Observed criterion σ(F): 0 / Redundancy: 3 % / Biso Wilson estimate: 15.8 Å2 / Rmerge(I) obs: 0.175 / Rsym value: 0.214 / Net I/σ(I): 7.1
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.303 / Mean I/σ(I) obs: 4.1 / Num. unique all: 1918 / Rsym value: 0.361 / % possible all: 99.3

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Processing

Software
NameVersionClassification
BSSdata collection
AMoREphasing
REFMAC5.5.0072refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3LCK

3lck


Resolution: 2.3→10 Å / Cor.coef. Fo:Fc: 0.88 / Cor.coef. Fo:Fc free: 0.757 / SU B: 9.855 / SU ML: 0.246 / Cross valid method: THROUGHOUT / ESU R: 0.611 / ESU R Free: 0.351 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.31819 1286 9.9 %RANDOM
Rwork0.21915 ---
obs0.22903 11695 97.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 23.975 Å2
Baniso -1Baniso -2Baniso -3
1--0.72 Å20 Å20 Å2
2--0.41 Å20 Å2
3---0.31 Å2
Refinement stepCycle: LAST / Resolution: 2.3→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2208 0 42 216 2466
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0222306
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0431.9853135
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9225270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.14423.761109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.28415395
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6741517
X-RAY DIFFRACTIONr_chiral_restr0.0740.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0211746
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.981.51352
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.7122190
X-RAY DIFFRACTIONr_scbond_it2.9233954
X-RAY DIFFRACTIONr_scangle_it4.2924.5942
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.357 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.375 99 -
Rwork0.218 820 -
obs--98.82 %

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