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- PDB-9nwx: Discovery of a Small Molecule ITK and Pan-TRK Kinase Inhibitor (P... -

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Basic information

Entry
Database: PDB / ID: 9nwx
TitleDiscovery of a Small Molecule ITK and Pan-TRK Kinase Inhibitor (PF-07245303) for the Potential Topical Treatment of Atopic Dermatitis
ComponentsTyrosine-protein kinase ITK/TSK
KeywordsSIGNALING PROTEIN / kinase / inhibitor / Atopic Dermatitis
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.348 Å
AuthorsLiu, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Discovery of a Small Molecule ITK and Pan-TRK Kinase Inhibitor (PF-07245303) for the Potential Topical Treatment of Atopic Dermatitis
Authors: Liu, S.
History
DepositionMar 24, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 19, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,0982
Polymers30,6491
Non-polymers4491
Water5,513306
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.23, 68.67, 49.51
Angle α, β, γ (deg.)90, 106.94, 90
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: 30649.004 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITK, EMT, LYK / Production host: Linospadix microcaryus (plant)
References: UniProt: Q08881, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-A1B66 / (2S)-N-methyl-N-{6-methyl-2-[(4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl]-1H-1,3-benzimidazol-5-yl}-2-(morpholin-4-yl)propanamide


Mass: 448.561 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H32N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 306 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.13 Å3/Da / Density % sol: 42.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 12% PEG 3350, 0.1 M magnesium acetate and 0.1 M HEPES, pH 7.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 29, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.348→38.38 Å / Num. obs: 38323 / % possible obs: 87.9 % / Redundancy: 3.2 % / CC1/2: 0.996 / Rmerge(I) obs: 0.08 / Rpim(I) all: 0.052 / Rrim(I) all: 0.096 / Net I/σ(I): 8.7
Reflection shellResolution: 1.355→1.46 Å / Rmerge(I) obs: 0.881 / Num. unique obs: 1915 / CC1/2: 0.393 / Rpim(I) all: 0.598 / Rrim(I) all: 1.07

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.348→26.34 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.94 / SU R Cruickshank DPI: 0.084 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.089 / SU Rfree Blow DPI: 0.093 / SU Rfree Cruickshank DPI: 0.09
RfactorNum. reflection% reflectionSelection details
Rfree0.2274 1884 -RANDOM
Rwork0.1822 ---
obs0.1844 38323 67.5 %-
Displacement parametersBiso mean: 19.73 Å2
Baniso -1Baniso -2Baniso -3
1--0.8979 Å20 Å2-0.112 Å2
2--0.3841 Å20 Å2
3---0.5138 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: LAST / Resolution: 1.348→26.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2115 0 33 306 2454
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0122331HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.123208HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d819SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes422HARMONIC5
X-RAY DIFFRACTIONt_it2261HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion287SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2626SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.03
X-RAY DIFFRACTIONt_other_torsion14.68
LS refinement shellResolution: 1.35→1.41 Å
RfactorNum. reflection% reflection
Rfree0.2873 30 -
Rwork0.2447 --
obs0.2463 767 11.23 %

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