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- PDB-4kio: Kinase domain mutant of human Itk in complex with a covalently-bi... -

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Basic information

Entry
Database: PDB / ID: 4kio
TitleKinase domain mutant of human Itk in complex with a covalently-binding 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 / activation of phospholipase C activity / 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 / activation of phospholipase C activity / 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 / metal ion binding / nucleus / 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-G5K / Chem-G6K / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.18 Å
AuthorsSomers, D.O.
CitationJournal: J.Biol.Chem. / Year: 2013
Title: Discovery of novel irreversible inhibitors of interleukin (IL)-2-inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket.
Authors: Harling, J.D. / Deakin, A.M. / Campos, S. / Grimley, R. / Chaudry, L. / Nye, C. / Polyakova, O. / Bessant, C.M. / Barton, N. / Somers, D. / Barrett, J. / Graves, R.H. / Hanns, L. / Kerr, W.J. / Solari, R.
History
DepositionMay 2, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 21, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2014Group: Database references

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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
C: Tyrosine-protein kinase ITK/TSK
D: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,67114
Polymers120,8584
Non-polymers2,81310
Water10,413578
1
A: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6812
Polymers30,2141
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6812
Polymers30,2141
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,4346
Polymers30,2141
Non-polymers1,2195
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,8754
Polymers30,2141
Non-polymers6613
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)69.309, 69.279, 141.852
Angle α, β, γ (deg.)90.00, 100.87, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#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.: 4 / Fragment: CATALYTIC DOMAIN / 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

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Non-polymers , 5 types, 588 molecules

#2: Chemical ChemComp-G5K / 1-[(3S)-3-{[4-(morpholin-4-ylmethyl)-6-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)pyrimidin-2-yl]amino}pyrrolidin-1-yl]prop-2-en-1-one


Mass: 466.559 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H26N8O2S
#3: Chemical ChemComp-G6K / 1-[(3S)-3-{[4-(morpholin-4-ylmethyl)-6-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)pyrimidin-2-yl]amino}pyrrolidin-1-yl]propan-1-one


Mass: 468.575 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H28N8O2S
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 578 / 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: 2.77 Å3/Da / Density % sol: 55.55 %
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, pH 5.7, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 30, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.18→54.039 Å / Num. all: 68592 / Num. obs: 68592 / % possible obs: 99.2 % / Redundancy: 2.9 % / Rsym value: 0.074 / Net I/σ(I): 10.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
2.18-2.32.90.35910.359199.8
2.3-2.442.90.2383.10.238199.8
2.44-2.612.90.1734.20.173199.7
2.61-2.812.90.1215.80.121199.6
2.81-3.082.90.0848.10.084199.5
3.08-3.452.90.0668.20.066198.9
3.45-3.982.90.0627.50.062198.5
3.98-4.872.80.0499.80.049197.7
4.87-6.892.80.04410.40.044198.7
6.89-54.0392.90.0385.90.038196.7

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.16data scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
REFMAC5.5.0109phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.18→20 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.954 / Occupancy max: 1 / Occupancy min: 0.41 / SU B: 8.974 / SU ML: 0.118 / SU R Cruickshank DPI: 0.1941 / Cross valid method: THROUGHOUT / ESU R: 0.194 / ESU R Free: 0.163 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20237 3473 5.1 %RANDOM
Rwork0.16534 ---
obs0.16725 65099 99.12 %-
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: 39.335 Å2
Baniso -1Baniso -2Baniso -3
1--0.18 Å2-0 Å2-1.44 Å2
2--1.97 Å20 Å2
3----1.41 Å2
Refinement stepCycle: LAST / Resolution: 2.18→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7681 0 191 578 8450
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0198210
X-RAY DIFFRACTIONr_bond_other_d0.0010.027497
X-RAY DIFFRACTIONr_angle_refined_deg1.5651.97511110
X-RAY DIFFRACTIONr_angle_other_deg0.815317276
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6725985
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.29823.611360
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.433151379
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9011552
X-RAY DIFFRACTIONr_chiral_restr0.0890.21185
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029333
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021848
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_it1.8022.4113934
X-RAY DIFFRACTIONr_mcbond_other1.7992.413933
X-RAY DIFFRACTIONr_mcangle_it2.8554.0354915
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.8712.8944276
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.18→2.236 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.273 238 -
Rwork0.227 4788 -
obs--99.74 %
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)
14.7921-4.67991.46667.8849-0.90852.21750.07270.50390.9747-0.6301-0.1636-0.6326-0.62310.47190.09090.2839-0.1270.04070.14360.08310.27512.02958.0089-10.6072
24.14910.34260.28793.02760.85493.31930.0898-0.22730.08870.2616-0.0507-0.1476-0.06740.2192-0.03910.0348-0.02420.00370.038-0.02020.058322.45530.360611.7647
35.15424.81311.70247.94560.68032.0456-0.1118-0.48121.0280.70830.0770.5242-0.6724-0.48680.03490.33620.19490.01790.1907-0.09510.39739.22711.772180.4427
43.7573-0.09110.74821.9281-0.66954.7455-0.0810.17160.0523-0.15470.11160.0533-0.327-0.1335-0.03060.085-0.03030.00020.06160.03810.0529-1.26054.98857.8572
52.1494-0.73080.20045.0222.59354.0220.0141-0.2639-0.64930.3195-0.08960.48060.5831-0.46630.07550.0998-0.04950.0070.11110.06440.2121-14.241214.13295.6302
62.6295-1.05361.26291.6161-1.08534.3954-0.0421-0.17-0.01150.09320.0242-0.0455-0.2483-0.03420.01790.04230.00350.0040.0181-0.00660.02980.222223.463725.1895
72.47491.2613-0.43455.1546-2.75584.2347-0.21130.1676-0.8308-0.33680.1599-0.45240.66350.47080.05140.15640.03170.05680.1859-0.08490.284235.807319.003165.0133
82.43040.77961.38281.44820.71565.2161-0.04310.2133-0.0452-0.10990.10740.0377-0.06040.1223-0.06430.1019-0.0994-0.00590.12250.02610.064422.360926.531344.2964
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A355 - 437
2X-RAY DIFFRACTION2A438 - 619
3X-RAY DIFFRACTION3B355 - 437
4X-RAY DIFFRACTION4B438 - 619
5X-RAY DIFFRACTION5C355 - 437
6X-RAY DIFFRACTION6C438 - 620
7X-RAY DIFFRACTION7D355 - 437
8X-RAY DIFFRACTION8D438 - 618

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