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- PDB-2zm4: Crystal structure of imidazo quinoxaline 1 bound to the kinase do... -

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Basic information

Entry
Database: PDB / ID: 2zm4
TitleCrystal structure of imidazo quinoxaline 1 bound to the kinase domain of human LCK, activated form (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 / Lipoprotein / Membrane / Myristate / Nucleotide-binding / Palmitate / Phosphoprotein / Proto-oncogene / SH2 domain / SH3 domain
Function / homology
Function and homology information


regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / CD27 signaling pathway / regulation of regulatory T cell differentiation / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / Fc-gamma receptor signaling pathway / FLT3 signaling through SRC family kinases / protein antigen binding / Nef Mediated CD4 Down-regulation ...regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / CD27 signaling pathway / regulation of regulatory T cell differentiation / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / Fc-gamma receptor signaling pathway / FLT3 signaling through SRC family kinases / protein antigen binding / Nef Mediated CD4 Down-regulation / intracellular zinc ion homeostasis / CD4 receptor binding / positive regulation of heterotypic cell-cell adhesion / Nef and signal transduction / Co-stimulation by CD28 / Interleukin-2 signaling / CD28 dependent Vav1 pathway / peptidyl-tyrosine autophosphorylation / Regulation of KIT signaling / leukocyte migration / phospholipase activator activity / Co-inhibition by CTLA4 / CD8 receptor binding / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / positive regulation of T cell receptor signaling pathway / pericentriolar material / protein serine/threonine phosphatase activity / PECAM1 interactions / hemopoiesis / Generation of second messenger molecules / RHOH GTPase cycle / T cell differentiation / immunological synapse / Co-inhibition by PD-1 / CD28 dependent PI3K/Akt signaling / T cell receptor binding / phospholipase binding / phosphatidylinositol 3-kinase binding / positive regulation of intrinsic apoptotic signaling pathway / GPVI-mediated activation cascade / T cell costimulation / release of sequestered calcium ion into cytosol / phosphotyrosine residue binding / SH2 domain binding / cell surface receptor protein tyrosine kinase signaling pathway / T cell activation / peptidyl-tyrosine phosphorylation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / Signaling by SCF-KIT / positive regulation of T cell activation / platelet activation / Constitutive Signaling by Aberrant PI3K in Cancer / cell-cell junction / Downstream TCR signaling / DAP12 signaling / PIP3 activates AKT signaling / T cell receptor signaling pathway / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / protein phosphorylation / intracellular signal transduction / membrane raft / response to xenobiotic stimulus / signaling receptor binding / positive regulation of gene expression / protein kinase binding / extracellular exosome / ATP binding / identical protein binding / plasma membrane / cytosol / cytoplasm
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-KSM / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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
DepositionApr 11, 2008Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 14, 2008Provider: 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 9, 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)33,7435
Polymers33,0661
Non-polymers6774
Water1,856103
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.591, 73.807, 92.159
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 / p56-LCK / Lymphocyte cell-specific protein-tyrosine kinase / 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


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-KSM / N-(2-chloro-6-methylphenyl)-8-[(3S)-3-methylpiperazin-1-yl]imidazo[1,5-a]quinoxalin-4-amine


Mass: 406.911 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23ClN6
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O
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: 2.19 Å3/Da / Density % sol: 43.84 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2M (NH4)2SO4, 0.1M Sodium Cacodylate, 30% PEG8000, 5.2% MPD, 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: Nov 10, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→28.44 Å / Num. all: 7521 / Num. obs: 8411 / % possible obs: 99.5 % / Redundancy: 3.4 % / Biso Wilson estimate: 31.6 Å2 / Rmerge(I) obs: 0.13 / Net I/σ(I): 10.2
Reflection shellResolution: 2.7→2.85 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.246 / Mean I/σ(I) obs: 5.3 / % possible all: 100

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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: 2.7→15 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.811 / SU B: 13.403 / SU ML: 0.276 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.43 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27447 811 9.7 %RANDOM
Rwork0.17607 ---
obs0.18583 7521 99.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 5.23 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å20 Å20 Å2
2--0.32 Å20 Å2
3---0.9 Å2
Refinement stepCycle: LAST / Resolution: 2.7→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2209 0 43 103 2355
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.0222308
X-RAY DIFFRACTIONr_angle_refined_deg2.2651.9893136
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4655270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.99123.796108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.52415394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.6231517
X-RAY DIFFRACTIONr_chiral_restr0.1370.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021752
X-RAY DIFFRACTIONr_nbd_refined0.250.21133
X-RAY DIFFRACTIONr_nbtor_refined0.3230.21511
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1960.2120
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.210.254
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1490.28
X-RAY DIFFRACTIONr_mcbond_it0.6331.51405
X-RAY DIFFRACTIONr_mcangle_it1.122192
X-RAY DIFFRACTIONr_scbond_it1.72331108
X-RAY DIFFRACTIONr_scangle_it2.7924.5944
LS refinement shellResolution: 2.7→2.768 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 47 -
Rwork0.225 539 -
obs--100 %

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