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- PDB-4ppc: ITK kinase domain with compound 27 (N-{1-[(1R)-3-(DIMETHYLAMINO)-... -

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Basic information

Entry
Database: PDB / ID: 4ppc
TitleITK kinase domain with compound 27 (N-{1-[(1R)-3-(DIMETHYLAMINO)-1-PHENYLPROPYL]-1H-PYRAZOL-4-YL}-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)
ComponentsTyrosine-protein kinase ITK/TSK
Keywordstransferase/transferase inhibitor / protein kinase / phospho-transfer / 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-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase ...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-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cell-cell junction / T cell receptor signaling pathway / adaptive immune response / intracellular signal transduction / signal transduction / zinc ion binding / ATP 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. ...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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-2VW / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsEigenbrot, C. / Shia, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors.
Authors: Pastor, R.M. / Burch, J.D. / Magnuson, S. / Ortwine, D.F. / Chen, Y. / De La Torre, K. / Ding, X. / Eigenbrot, C. / Johnson, A. / Liimatta, M. / Liu, Y. / Shia, S. / Wang, X. / Wu, L.C. / Pei, Z.
History
DepositionFeb 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 4, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2018Group: Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
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
B: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,3384
Polymers60,4292
Non-polymers9092
Water00
1
A: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6692
Polymers30,2141
Non-polymers4551
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6692
Polymers30,2141
Non-polymers4551
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4220 Å2
ΔGint-34 kcal/mol
Surface area23150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.456, 97.221, 134.806
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: kinase 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
#2: Chemical ChemComp-2VW / N-{1-[(1R)-3-(dimethylamino)-1-phenylpropyl]-1H-pyrazol-4-yl}-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide


Mass: 454.527 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H26N8O

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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: 2.14 Å3/Da / Density % sol: 42.5 %
Crystal growTemperature: 280 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: sodium nitrate, PEG3350, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 380K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 23, 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: 2.95→55.4 Å / Num. all: 11471 / Num. obs: 11371 / % possible obs: 98.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.4 % / Biso Wilson estimate: 66.14 Å2 / Rsym value: 0.147 / Net I/σ(I): 13.1

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1SM2

1sm2


Resolution: 2.95→55.39 Å / Cor.coef. Fo:Fc: 0.9038 / Cor.coef. Fo:Fc free: 0.8619
Isotropic thermal model: individual atomic plus TLS in two groups
Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2568 564 4.96 %RANDOM
Rwork0.2128 ---
obs0.215 11371 98.63 %-
all-11471 --
Displacement parametersBiso mean: 55.36 Å2
Baniso -1Baniso -2Baniso -3
1--5.994 Å20 Å20 Å2
2--9.0694 Å20 Å2
3----3.0754 Å2
Refine analyzeLuzzati coordinate error obs: 0.395 Å
Refinement stepCycle: LAST / Resolution: 2.95→55.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3698 0 68 0 3766
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0073865HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.945220HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1334SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes88HARMONIC2
X-RAY DIFFRACTIONt_gen_planes554HARMONIC5
X-RAY DIFFRACTIONt_it3865HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.13
X-RAY DIFFRACTIONt_other_torsion19.43
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion475SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4354SEMIHARMONIC4
LS refinement shellResolution: 2.95→3.23 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.251 159 5.94 %
Rwork0.217 2516 -
all0.219 2675 -
obs--98.63 %
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)
10.3859-0.38630.2991.4179-0.87650.9225-0.01020.07880.03310.0986-0.0195-0.12860.01590.07950.0297-0.06140.0047-0.0381-0.14030.00870.012122.3919-15.3598-45.1306
20.1422-0.14770.00371.37860.94161.26220.02710.00130.0002-0.0432-0.02760.02050.07550.0040.0004-0.0415-0.0129-0.0007-0.139-0.0028-0.012118.6153-12.0853-16.7759
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|356 - A|619 A|701 - A|701 }A356 - 619
2X-RAY DIFFRACTION1{ A|356 - A|619 A|701 - A|701 }A701
3X-RAY DIFFRACTION2{ B|356 - B|619 B|701 - B|701 }B356 - 619
4X-RAY DIFFRACTION2{ B|356 - B|619 B|701 - B|701 }B701

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