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- PDB-4l7s: Kinase domain mutant of human Itk in complex with an aminobenzoth... -

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Basic information

Entry
Database: PDB / ID: 4l7s
TitleKinase domain mutant of human Itk in complex with an aminobenzothiazole inhibitor
ComponentsTyrosine-protein kinase ITK/TSK
KeywordsTransferase/Transferase inhibitor / KINASE DOMAIN / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


gamma-delta T cell activation / NK T cell differentiation / : / Generation of second messenger molecules / cellular defense response / T cell activation / FCERI mediated Ca+2 mobilization / positive regulation of cytokine production / B cell receptor signaling pathway / non-specific protein-tyrosine kinase ...gamma-delta T cell activation / NK T cell differentiation / : / Generation of second messenger molecules / cellular defense response / T cell activation / FCERI mediated Ca+2 mobilization / 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 / phosphorylation / 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. / 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 / 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-G7K / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.03 Å
AuthorsSomers, D.O.
CitationJournal: ACS Med Chem Lett / Year: 2013
Title: Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy.
Authors: Alder, C.M. / Ambler, M. / Campbell, A.J. / Champigny, A.C. / Deakin, A.M. / Harling, J.D. / Harris, C.A. / Longstaff, T. / Lynn, S. / Maxwell, A.C. / Mooney, C.J. / Scullion, C. / Singh, O. ...Authors: Alder, C.M. / Ambler, M. / Campbell, A.J. / Champigny, A.C. / Deakin, A.M. / Harling, J.D. / Harris, C.A. / Longstaff, T. / Lynn, S. / Maxwell, A.C. / Mooney, C.J. / Scullion, C. / Singh, O.M. / Smith, I.E. / Somers, D.O. / Tame, C.J. / Wayne, G. / Wilson, C. / Woolven, J.M.
History
DepositionJun 14, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase ITK/TSK
B: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,5585
Polymers60,4292
Non-polymers1,1293
Water7,296405
1
A: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,7312
Polymers30,2141
Non-polymers5171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,8273
Polymers30,2141
Non-polymers6132
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2790 Å2
ΔGint-15 kcal/mol
Surface area20910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.857, 69.523, 68.617
Angle α, β, γ (deg.)90.000, 108.180, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-902-

HOH

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Components

#1: Protein Tyrosine-protein kinase ITK/TSK / Interleukin-2-inducible T-cell kinase / IL-2-inducible T-cell kinase / Kinase EMT / T-cell-specific ...Interleukin-2-inducible T-cell kinase / IL-2-inducible T-cell kinase / Kinase EMT / T-cell-specific kinase / Tyrosine-protein kinase Lyk


Mass: 30214.492 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN (UNP residues 357-620) / Mutation: Y512E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITK, EMT, LYK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q08881, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-G7K / trans-4-({4-[difluoro(4-fluorophenyl)methyl]-6-[(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)amino]pyrimidin-2-yl}amino)cyclohexanol


Mass: 516.539 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23F3N6O2S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 405 / 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: 2.75 Å3/Da / Density % sol: 55.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.7
Details: 0.85M ammonium sulphate, 0.2M magnesium acetate, 0.1M sodium citrate, 10mM dithiothreitol (See citation for full details), pH 5.7, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0332 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 18, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.03→69.843 Å / Num. all: 42515 / Num. obs: 42515 / % possible obs: 99.9 % / Redundancy: 3.6 % / Biso Wilson estimate: 28.3 Å2 / Rmerge(I) obs: 0.149 / Rsym value: 0.149 / Net I/σ(I): 8.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.03-2.143.60.4941.42249961730.494100
2.14-2.273.60.3392.12122758450.339100
2.27-2.433.60.2532.71998155050.253100
2.43-2.623.60.1993.31870251620.199100
2.62-2.873.60.1693.51694147060.169100
2.87-3.213.60.1493.71530942690.149100
3.21-3.713.50.134.11321037790.1399.9
3.71-4.543.20.1174.61040532160.117100
4.54-6.423.60.1194.4903925060.119100
6.42-69.8433.20.1184.3435813540.11896.7

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.2.21data scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
REFMAC5.5.0038phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.03→20 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.936 / WRfactor Rfree: 0.2253 / WRfactor Rwork: 0.1758 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8643 / SU B: 8.103 / SU ML: 0.119 / SU R Cruickshank DPI: 0.1572 / SU Rfree: 0.1517 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.157 / ESU R Free: 0.152 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2214 2146 5 %RANDOM
Rwork0.1717 ---
obs0.1742 42514 99.85 %-
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 max: 116.87 Å2 / Biso mean: 45.699 Å2 / Biso min: 7.84 Å2
Baniso -1Baniso -2Baniso -3
1--1.45 Å20 Å20.63 Å2
2--1.48 Å2-0 Å2
3----0.19 Å2
Refinement stepCycle: LAST / Resolution: 2.03→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3916 0 77 405 4398
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0194134
X-RAY DIFFRACTIONr_bond_other_d0.0020.023843
X-RAY DIFFRACTIONr_angle_refined_deg1.4981.9555606
X-RAY DIFFRACTIONr_angle_other_deg0.8238850
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7595506
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.51323.743179
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.53515693
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.691524
X-RAY DIFFRACTIONr_chiral_restr0.0890.2608
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024635
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02951
X-RAY DIFFRACTIONr_mcbond_it1.8622.5692018
X-RAY DIFFRACTIONr_mcbond_other1.8582.5672017
X-RAY DIFFRACTIONr_mcangle_it2.8924.3062523
LS refinement shellResolution: 2.03→2.082 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 135 -
Rwork0.25 2960 -
all-3095 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.8728-2.2326-1.28677.05394.67854.70110.15740.53040.779-0.8548-0.1541-0.0546-1.0371-0.2071-0.00340.24780.0362-0.02060.12430.17370.270320.1618.91717.523
26.34511.7520.09873.33370.46843.9942-0.06490.23410.23630.0351-0.1564-0.3026-0.12630.27940.22130.0451-0.01360.00270.05050.06080.087244.0110.20815.258
35.3094-4.40161.28586.8013-2.50272.1850.1180.6889-0.7303-0.4394-0.26430.17270.7469-0.38840.14630.2993-0.20960.08880.2608-0.17990.172924.76-20.44217.22
46.2534-0.45990.32771.8648-1.47546.70420.07-0.1216-0.3853-0.05230.12020.24250.3202-1.0208-0.19010.0231-0.0525-0.01810.16470.02470.08112.193-10.9424.89
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A355 - 437
2X-RAY DIFFRACTION2A438 - 620
3X-RAY DIFFRACTION3B355 - 437
4X-RAY DIFFRACTION4B438 - 620

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