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- PDB-3ad5: Crystal structure of Triazolone derivative bound to the kinase do... -

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Basic information

Entry
Database: PDB / ID: 3ad5
TitleCrystal structure of Triazolone 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 / 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 / Nef and signal transduction / CD4 receptor binding / Nef Mediated CD4 Down-regulation / 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 / Nef and signal transduction / CD4 receptor binding / Nef Mediated CD4 Down-regulation / positive regulation of heterotypic cell-cell adhesion / Interleukin-2 signaling / CD28 dependent Vav1 pathway / Regulation of KIT signaling / leukocyte migration / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / phospholipase activator activity / CD8 receptor binding / pericentriolar material / positive regulation of T cell receptor signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / PECAM1 interactions / CD28 dependent PI3K/Akt signaling / phospholipase binding / hemopoiesis / RHOH GTPase cycle / 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 / cell surface receptor protein tyrosine kinase signaling pathway / GPVI-mediated activation cascade / release of sequestered calcium ion into cytosol / T cell costimulation / phosphotyrosine residue binding / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / non-specific protein-tyrosine kinase / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / Signaling by SCF-KIT / : / platelet activation / peptidyl-tyrosine phosphorylation / 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 tyrosine kinase activity / protein phosphatase binding / intracellular signal transduction / response to xenobiotic stimulus / protein phosphorylation / membrane raft / innate immune response / signaling receptor binding / 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 ...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 / 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-5PB / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 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
DepositionJan 14, 2010Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 19, 2011Provider: 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
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)33,9066
Polymers33,0661
Non-polymers8405
Water5,513306
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.961, 73.610, 91.960
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Proto-oncogene tyrosine-protein kinase LCK / LYMPHOCYTE KINASE / Lymphocyte cell-specific protein-tyrosine kinase / p56-LCK / LSK / T cell- ...LYMPHOCYTE KINASE / Lymphocyte cell-specific protein-tyrosine kinase / p56-LCK / LSK / T cell-specific protein-tyrosine kinase


Mass: 33065.602 Da / Num. of mol.: 1 / Fragment: RESIDUES 225-509
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LCK / Plasmid: PET-19B / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P06239, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 311 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Chemical ChemComp-5PB / 4-[4-(benzyloxy)phenyl]-5-{[2-(4-chlorophenyl)-2-oxoethyl]sulfanyl}-2,4-dihydro-3H-1,2,4-triazol-3-one


Mass: 451.925 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18ClN3O3S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 306 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.15 Å3/Da / Density % sol: 42.73 %
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: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32B2 / Wavelength: 1 Å
DetectorType: RIGAKU JUPITER 210 / Detector: CCD / Date: Nov 12, 2002
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→41.96 Å / Num. all: 19902 / Num. obs: 19948 / % possible obs: 100 % / Observed criterion σ(F): 0 / Redundancy: 7.1 % / Biso Wilson estimate: 18.6 Å2 / Rmerge(I) obs: 0.059 / Rsym value: 0.064 / Net I/σ(I): 25.7
Reflection shellResolution: 2→2.11 Å / Redundancy: 7.3 % / Rmerge(I) obs: 0.128 / Mean I/σ(I) obs: 14.3 / Num. unique all: 2872 / Rsym value: 0.137 / % possible all: 100

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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→10 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.903 / SU B: 3.453 / SU ML: 0.1 / Cross valid method: THROUGHOUT / ESU R: 0.188 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21845 2010 10.2 %RANDOM
Rwork0.1543 ---
obs0.16081 17695 99.97 %-
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: 14.811 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å20 Å20 Å2
2--0.02 Å20 Å2
3---0.36 Å2
Refinement stepCycle: LAST / Resolution: 2→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2212 0 53 306 2571
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222318
X-RAY DIFFRACTIONr_angle_refined_deg1.3771.9873146
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.655270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.34623.761109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.78815395
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5691517
X-RAY DIFFRACTIONr_chiral_restr0.0860.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.0211759
X-RAY DIFFRACTIONr_mcbond_it1.4851.51356
X-RAY DIFFRACTIONr_mcangle_it2.38722196
X-RAY DIFFRACTIONr_scbond_it3.883962
X-RAY DIFFRACTIONr_scangle_it5.8484.5950
LS refinement shellResolution: 2→2.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.23 157 -
Rwork0.135 1226 -
obs--99.86 %

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