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- PDB-3mj2: X-ray crystal structure of ITK complexed with inhibitor BMS-509744 -

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Basic information

Entry
Database: PDB / ID: 3mj2
TitleX-ray crystal structure of ITK complexed with inhibitor BMS-509744
ComponentsTyrosine-protein kinase ITK/TSK
KeywordsTRANSFERASE / helix C-out / substrate blocking activation loop conformation
Function / homology
Function and homology information


NK T cell differentiation / gamma-delta T cell activation / Generation of second messenger molecules / cellular defense response / FCERI mediated Ca+2 mobilization / T cell activation / positive regulation of cytokine production / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity ...NK T cell differentiation / gamma-delta T cell activation / Generation of second messenger molecules / cellular defense response / FCERI mediated Ca+2 mobilization / T cell activation / positive regulation of cytokine production / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cell-cell junction / T cell receptor signaling pathway / adaptive immune response / intracellular signal transduction / signal transduction / ATP binding / nucleus / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase ITK, SH3 domain / Tyrosine-protein kinase ITK/TSK, catalytic domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / : / PH domain / PH domain profile. / Pleckstrin homology domain. ...Tyrosine-protein kinase ITK, SH3 domain / Tyrosine-protein kinase ITK/TSK, catalytic domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / : / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology 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. / PH-like domain superfamily / 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-MJG / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsKuglstatter, A. / Villasenor, A.G.
CitationJournal: Chem.Biol.Drug Des. / Year: 2010
Title: Crystal structures of IL-2-inducible T cell kinase complexed with inhibitors: insights into rational drug design and activity regulation.
Authors: Kutach, A.K. / Villasenor, A.G. / Lam, D. / Belunis, C. / Janson, C. / Lok, S. / Hong, L.N. / Liu, C.M. / Deval, J. / Novak, T.J. / Barnett, J.W. / Chu, W. / Shaw, D. / Kuglstatter, A.
History
DepositionApr 12, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 30, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Oct 6, 2021Group: Database references / Derived calculations / Category: 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 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / 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 ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,7402
Polymers30,1161
Non-polymers6241
Water3,009167
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)121.082, 39.246, 50.860
Angle α, β, γ (deg.)90.00, 93.69, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Tyrosine-protein kinase ITK/TSK / T-cell-specific kinase / Tyrosine-protein kinase Lyk / Kinase EMT


Mass: 30116.418 Da / Num. of mol.: 1 / Fragment: UNP residues 357-620 / Mutation: C477S, E614A, E617A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITK, EMT, LYK / Plasmid: pVL / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9 II SFM
References: UniProt: Q08881, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-MJG / N-[5-({5-[(4-acetylpiperazin-1-yl)carbonyl]-4-methoxy-2-methylphenyl}sulfanyl)-1,3-thiazol-2-yl]-4-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)benzamide


Mass: 623.829 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H41N5O4S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / 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 Å3/Da / Density % sol: 38.56 %
Crystal growTemperature: 283 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 20% PEG3350, 0.2m ammonium acetate, 0.1M Bis-Tris, pH 6.0, VAPOR DIFFUSION, SITTING DROP, temperature 283K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→37.7 Å / Num. all: 19376 / Num. obs: 17785 / % possible obs: 91.8 % / Rsym value: 0.07 / Net I/σ(I): 13.5
Reflection shellResolution: 1.9→1.97 Å / Mean I/σ(I) obs: 2.1 / Num. unique all: 1336 / Rsym value: 0.283 / % possible all: 55.2

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 3MIY

3miy


Resolution: 1.9→37.7 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.922 / SU B: 9.374 / SU ML: 0.126 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.221 / ESU R Free: 0.183 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25189 909 5.1 %RANDOM
Rwork0.20565 ---
obs0.20803 16876 93.24 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 24.864 Å2
Baniso -1Baniso -2Baniso -3
1-1.59 Å20 Å20.08 Å2
2---0.64 Å20 Å2
3----0.95 Å2
Refinement stepCycle: LAST / Resolution: 1.9→37.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2074 0 43 167 2284
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222169
X-RAY DIFFRACTIONr_angle_refined_deg1.0061.9782936
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2815258
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.46823.7100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.51715371
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7211514
X-RAY DIFFRACTIONr_chiral_restr0.0760.2313
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021651
X-RAY DIFFRACTIONr_nbd_refined0.1840.21068
X-RAY DIFFRACTIONr_nbtor_refined0.3030.21494
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1240.2179
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1860.258
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1380.217
X-RAY DIFFRACTIONr_mcbond_it0.5111.51336
X-RAY DIFFRACTIONr_mcangle_it0.8922079
X-RAY DIFFRACTIONr_scbond_it1.1113976
X-RAY DIFFRACTIONr_scangle_it1.7834.5857
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 45 -
Rwork0.249 720 -
obs--54.14 %
Refinement TLS params.Method: refined / Origin x: 16.4737 Å / Origin y: -1.4235 Å / Origin z: 7.1347 Å
111213212223313233
T0.0025 Å20.0063 Å20.004 Å2--0.0074 Å20.0024 Å2--0.0042 Å2
L0.5175 °20.2474 °20.3798 °2-0.2223 °2-0.0029 °2--0.606 °2
S0.0229 Å °0.04 Å °-0.046 Å °0.0001 Å °-0.0107 Å °-0.046 Å °0.0096 Å °0.0152 Å °-0.0122 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1001 - 4063
2X-RAY DIFFRACTION1A1
3X-RAY DIFFRACTION1A357 - 615

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