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- PDB-4pp9: ITK kinase domain with compound 1 (N-[1-(3-CYANOBENZYL)-1H-PYRAZO... -

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Basic information

Entry
Database: PDB / ID: 4pp9
TitleITK kinase domain with compound 1 (N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-2H-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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-2VT / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 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)61,3066
Polymers60,4292
Non-polymers8774
Water1,33374
1
A: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,7494
Polymers30,2141
Non-polymers5343
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,5572
Polymers30,2141
Non-polymers3421
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3160 Å2
ΔGint-37 kcal/mol
Surface area21820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.039, 104.090, 57.313
Angle α, β, γ (deg.)90.00, 110.21, 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: 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-2VT / N-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]-2H-indazole-3-carboxamide


Mass: 342.354 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H14N6O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / 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: 2.55 Å3/Da / Density % sol: 51.76 %
Crystal growTemperature: 280 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: sodium nitrate, PEG3350, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 380K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 30, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→40 Å / Num. all: 17994 / Num. obs: 17975 / % possible obs: 92.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.4 % / Biso Wilson estimate: 48.64 Å2 / Rsym value: 0.148 / Net I/σ(I): 7.9

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
BUSTER2.11.4refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1SM2

1sm2


Resolution: 2.58→25.34 Å / Cor.coef. Fo:Fc: 0.9064 / Cor.coef. Fo:Fc free: 0.8591 / SU R Cruickshank DPI: 0.903
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
Rfree0.2837 919 5.11 %RANDOM
Rwork0.2229 ---
obs0.226 17975 94.04 %-
all-17994 --
Displacement parametersBiso mean: 44.32 Å2
Baniso -1Baniso -2Baniso -3
1--1.0059 Å20 Å21.4588 Å2
2--11.4973 Å20 Å2
3----10.4914 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: LAST / Resolution: 2.58→25.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3932 0 62 74 4068
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084086HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.025518HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1418SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes100HARMONIC2
X-RAY DIFFRACTIONt_gen_planes589HARMONIC5
X-RAY DIFFRACTIONt_it4086HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.48
X-RAY DIFFRACTIONt_other_torsion21.23
X-RAY DIFFRACTIONt_chiral_improper_torsion497SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4663SEMIHARMONIC4
LS refinement shellResolution: 2.58→2.74 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3032 130 5.9 %
Rwork0.2386 2072 -
all0.2421 2202 -
obs--94.04 %
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)
11.1763-0.48080.28491.97770.57660.5809-0.03690.0754-0.0311-0.00590.0482-0.01010.0923-0.0135-0.0113-0.1831-0.0255-0.0036-0.0860.01890.093-1.22230.8609-18.4588
21.0028-0.649-0.26842.265-0.48990.4031-0.03730.06620.05190.05980.0160.026-0.08530.04790.0214-0.1879-0.0133-0.0574-0.0905-0.01660.1119-6.404633.2053-18.3626
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|357 - A|619 A|703 - A|703 }A357 - 619
2X-RAY DIFFRACTION1{ A|357 - A|619 A|703 - A|703 }A703
3X-RAY DIFFRACTION2{ B|357 - B|619 B|701 - B|701 }B357 - 619
4X-RAY DIFFRACTION2{ B|357 - B|619 B|701 - B|701 }B701

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