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- PDB-4pqn: ITK kinase domain with compound GNE-9822 -

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Basic information

Entry
Database: PDB / ID: 4pqn
TitleITK kinase domain with compound GNE-9822
ComponentsTyrosine-protein kinase ITK/TSK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / phospho-transfer / 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-2W6 / 1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 Å
AuthorsMcEwan, P.A. / Barker, J.J. / Eigenbrot, C.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors.
Authors: Burch, J.D. / Lau, K. / Barker, J.J. / Brookfield, F. / Chen, Y. / Chen, Y. / Eigenbrot, C. / Ellebrandt, C. / Ismaili, M.H. / Johnson, A. / Kordt, D. / MacKinnon, C.H. / McEwan, P.A. / ...Authors: Burch, J.D. / Lau, K. / Barker, J.J. / Brookfield, F. / Chen, Y. / Chen, Y. / Eigenbrot, C. / Ellebrandt, C. / Ismaili, M.H. / Johnson, A. / Kordt, D. / MacKinnon, C.H. / McEwan, P.A. / Ortwine, D.F. / Stein, D.B. / Wang, X. / Winkler, D. / Yuen, P.W. / Zhang, Y. / Zarrin, A.A. / Pei, Z.
History
DepositionMar 3, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 2, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 23, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)30,6993
Polymers30,1161
Non-polymers5832
Water3,999222
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)120.180, 39.030, 50.680
Angle α, β, γ (deg.)90.00, 93.07, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-888-

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: 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-2W6 / N-{1-[(1S)-3-(dimethylamino)-1-phenylpropyl]-1H-pyrazol-4-yl}-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide


Mass: 420.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32N6O
#3: Chemical ChemComp-P4G / 1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE / Diethylene glycol diethyl ether


Mass: 162.227 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 222 / 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: 1.97 Å3/Da / Density % sol: 37.58 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: PEG6000, NaCl, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 2, 2011
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.71→50.6 Å / Num. all: 25458 / Num. obs: 25457 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 13.3

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
REFMAC5.8.0049refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1SM2

1sm2


Resolution: 1.71→50.6 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.944 / SU B: 4.856 / SU ML: 0.079
Isotropic thermal model: individual atomic plus TLS in one group
Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.108 / ESU R Free: 0.108 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20164 1295 5.1 %RANDOM
Rwork0.15906 ---
obs0.16125 24162 99.15 %-
all-25163 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.611 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å20 Å2-0.19 Å2
2--0.73 Å20 Å2
3----0.32 Å2
Refine analyzeLuzzati coordinate error obs: 0.1 Å
Refinement stepCycle: LAST / Resolution: 1.71→50.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1919 0 42 222 2183
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0192103
X-RAY DIFFRACTIONr_bond_other_d0.0010.022013
X-RAY DIFFRACTIONr_angle_refined_deg1.9831.9972855
X-RAY DIFFRACTIONr_angle_other_deg0.9434643
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1895257
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.70423.54296
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.89315364
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3871515
X-RAY DIFFRACTIONr_chiral_restr0.120.2306
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.022334
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02497
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_it2.2361.623977
X-RAY DIFFRACTIONr_mcbond_other2.2331.622976
X-RAY DIFFRACTIONr_mcangle_it3.6332.4111221
X-RAY DIFFRACTIONr_mcangle_other3.6332.4121222
X-RAY DIFFRACTIONr_scbond_it2.6621.8611126
X-RAY DIFFRACTIONr_scbond_other2.6611.8611127
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.1922.6661625
X-RAY DIFFRACTIONr_long_range_B_refined6.94113.9392564
X-RAY DIFFRACTIONr_long_range_B_other6.9413.9422565
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.71→1.754 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 75 -
Rwork0.245 1813 -
obs--99.84 %
Refinement TLS params.Method: refined / Origin x: -17.0536 Å / Origin y: 9.7287 Å / Origin z: 17.8311 Å
111213212223313233
T0.029 Å20.0012 Å2-0.0016 Å2-0.0198 Å2-0.0006 Å2--0.0018 Å2
L0.4446 °2-0.1118 °20.1259 °2-0.035 °20.0049 °2--0.2529 °2
S-0.0033 Å °-0.01 Å °-0.0245 Å °0.0051 Å °0.0006 Å °0.0074 Å °0.0002 Å °-0.0302 Å °0.0027 Å °

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