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- PDB-4rfm: ITK kinase domain in complex with compound 1 N-{1-[(1,1-dioxo-1-t... -

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Basic information

Entry
Database: PDB / ID: 4rfm
TitleITK kinase domain in complex with compound 1 N-{1-[(1,1-dioxo-1-thian-2-yl)(phenyl)methyl]-1H- pyrazol-4-yl}-5,5-difluoro-5a-methyl-1H,4H,4aH,5H,5aH,6H-cyclopropa[f]indazole-3-carboxamide
ComponentsTyrosine-protein kinase ITK/TSK
KeywordsTRANSFERASE/INHIBITOR / kinase / 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-3P6 / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsMcEwan, P.A. / Barker, J.J. / Eigenbrot, C.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo.
Authors: Burch, J.D. / Barrett, K. / Chen, Y. / DeVoss, J. / Eigenbrot, C. / Goldsmith, R. / Ismaili, M.H. / Lau, K. / Lin, Z. / Ortwine, D.F. / Zarrin, A.A. / McEwan, P.A. / Barker, J.J. / ...Authors: Burch, J.D. / Barrett, K. / Chen, Y. / DeVoss, J. / Eigenbrot, C. / Goldsmith, R. / Ismaili, M.H. / Lau, K. / Lin, Z. / Ortwine, D.F. / Zarrin, A.A. / McEwan, P.A. / Barker, J.J. / Ellebrandt, C. / Kordt, D. / Stein, D.B. / Wang, X. / Chen, Y. / Hu, B. / Xu, X. / Yuen, P.W. / Zhang, Y. / Pei, Z.
History
DepositionSep 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2015Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6322
Polymers30,1161
Non-polymers5161
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.006, 69.561, 47.347
Angle α, β, γ (deg.)90.00, 113.39, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 1 / Fragment: kinase domain (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 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q08881, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-3P6 / (4aS,5aR)-N-{1-[(R)-[(2R)-1,1-dioxidotetrahydro-2H-thiopyran-2-yl](phenyl)methyl]-1H-pyrazol-4-yl}-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide


Mass: 515.575 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27F2N5O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.01 Å3/Da / Density % sol: 38.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M Magnesium Chloride, 0.1 M Tris.HCl (pH 8.0), 20 % PEG 6000, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5419 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jan 1, 2013
RadiationMonochromator: Confocal optics / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5419 Å / Relative weight: 1
ReflectionResolution: 2.1→32.47 Å / Num. obs: 13527 / % possible obs: 96.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0

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Processing

Software
NameVersionClassification
CrystalCleardata collection
PHASERphasing
REFMAC5.7.0032refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→32.47 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.933 / SU B: 12.413 / SU ML: 0.17 / Cross valid method: THROUGHOUT / ESU R: 0.307 / ESU R Free: 0.232 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26362 675 5 %RANDOM
Rwork0.20265 ---
obs0.20569 12851 96.86 %-
all-13960 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.73 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20 Å2
2---0 Å2-0 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.1→32.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1977 0 36 87 2100
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0192087
X-RAY DIFFRACTIONr_bond_other_d0.0010.021956
X-RAY DIFFRACTIONr_angle_refined_deg1.7761.9762833
X-RAY DIFFRACTIONr_angle_other_deg0.91634503
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2045251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.96523.47495
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.59915354
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.841514
X-RAY DIFFRACTIONr_chiral_restr0.1050.2302
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022360
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02500
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_it2.4922.9181001
X-RAY DIFFRACTIONr_mcbond_other2.4932.9161000
X-RAY DIFFRACTIONr_mcangle_it3.7054.3581250
X-RAY DIFFRACTIONr_mcangle_other3.7044.361251
X-RAY DIFFRACTIONr_scbond_it3.0063.2521086
X-RAY DIFFRACTIONr_scbond_other3.0063.2521085
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.5784.7461580
X-RAY DIFFRACTIONr_long_range_B_refined6.54723.862390
X-RAY DIFFRACTIONr_long_range_B_other6.54623.8672391
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.347 36 -
Rwork0.27 686 -
obs--72.2 %
Refinement TLS params.Method: refined / Origin x: 9.2519 Å / Origin y: 0.1574 Å / Origin z: 13.9453 Å
111213212223313233
T0.0359 Å20.0004 Å2-0.0162 Å2-0.0454 Å2-0.0141 Å2--0.056 Å2
L0.7168 °20.1263 °2-0.3278 °2-0.6151 °2-0.1433 °2--0.3178 °2
S0.0053 Å °0.0374 Å °-0.0021 Å °-0.0531 Å °0.0221 Å °0.019 Å °-0.0239 Å °-0.0291 Å °-0.0274 Å °

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