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- PDB-4mf1: ITK kinase domain in complex with benzothiazole inhibitor 12b (1S... -

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Basic information

Entry
Database: PDB / ID: 4mf1
TitleITK kinase domain in complex with benzothiazole inhibitor 12b (1S,2S)-2-{4-[(DIMETHYLAMINO)METHYL]PHENYL}-N-[6-(1H-PYRAZOL-4-YL)-1,3-BENZOTHIAZOL-2-YL]CYCLOPROPANECARBOXAMIDE
ComponentsTyrosine-protein kinase ITK/TSK
Keywordstransferase/transferase inhibitor / protein kinase / phosphotransfer catalyst / transferase-transferase inhibitor complex
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-29Y / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.113 Å
AuthorsEigenbrot, C. / Shia, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).
Authors: Mackinnon, C.H. / Lau, K. / Burch, J.D. / Chen, Y. / Dines, J. / Ding, X. / Eigenbrot, C. / Heifetz, A. / Jaochico, A. / Johnson, A. / Kraemer, J. / Kruger, S. / Krulle, T.M. / Liimatta, M. ...Authors: Mackinnon, C.H. / Lau, K. / Burch, J.D. / Chen, Y. / Dines, J. / Ding, X. / Eigenbrot, C. / Heifetz, A. / Jaochico, A. / Johnson, A. / Kraemer, J. / Kruger, S. / Krulle, T.M. / Liimatta, M. / Ly, J. / Maghames, R. / Montalbetti, C.A. / Ortwine, D.F. / Perez-Fuertes, Y. / Shia, S. / Stein, D.B. / Trani, G. / Vaidya, D.G. / Wang, X. / Bromidge, S.M. / Wu, L.C. / Pei, Z.
History
DepositionAug 27, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 13, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2013Group: 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

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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)61,0684
Polymers60,2332
Non-polymers8352
Water5,044280
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2770 Å2
ΔGint-4 kcal/mol
Surface area21310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.842, 51.745, 66.199
Angle α, β, γ (deg.)99.01, 104.62, 92.31
Int Tables number1
Space group name H-MP1
DetailsThe asymmetric unit contains two kinase domains. The activity biological assembly is understood to be a single kinase domain.

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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: 30116.418 Da / Num. of mol.: 2 / Fragment: unp residues 357-620 / Mutation: C477S, E614A, E617A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EMT, ITK, LYK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q08881, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-29Y / (1S,2S)-2-{4-[(dimethylamino)methyl]phenyl}-N-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide


Mass: 417.527 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23N5OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 280 / 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: 2.16 Å3/Da / Density % sol: 43 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 6
Details: PEG6000, 0.2M NaCl, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 28, 2011
RadiationMonochromator: Asymmetric curved crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.13→30 Å / Num. all: 26914 / Num. obs: 26887 / % possible obs: 95.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 1.9 % / Biso Wilson estimate: 22 Å2 / Rsym value: 0.062 / Net I/σ(I): 12

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.113→29.881 Å / SU ML: 0.29 / σ(F): 1.98 / Phase error: 24.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2286 864 3.21 %random
Rwork0.175 ---
obs0.1768 26887 93.73 %-
all-26914 --
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 42.527 Å2 / ksol: 0.345 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.2465 Å20.8767 Å2-5.6315 Å2
2---4.2222 Å2-8.3731 Å2
3---2.9757 Å2
Refinement stepCycle: LAST / Resolution: 2.113→29.881 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3873 0 60 280 4213
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074039
X-RAY DIFFRACTIONf_angle_d1.0135460
X-RAY DIFFRACTIONf_dihedral_angle_d14.521466
X-RAY DIFFRACTIONf_chiral_restr0.073591
X-RAY DIFFRACTIONf_plane_restr0.004692
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1173-2.24990.30151500.20673564X-RAY DIFFRACTION77
2.2499-2.42350.22041350.18464377X-RAY DIFFRACTION95
2.4235-2.66730.29481250.17834556X-RAY DIFFRACTION98
2.6673-3.05290.2231500.18434516X-RAY DIFFRACTION98
3.0529-3.8450.22241440.16344498X-RAY DIFFRACTION97
3.845-29.8840.1951600.1674512X-RAY DIFFRACTION98

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