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- PDB-4qt1: JAK3 kinase domain in complex with 1-[(3S)-1-isobutylsulfonyl-3-p... -

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Basic information

Entry
Database: PDB / ID: 4qt1
TitleJAK3 kinase domain in complex with 1-[(3S)-1-isobutylsulfonyl-3-piperidyl]-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)urea
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase-Inhibitor Complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine production / : / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / tyrosine phosphorylation of STAT protein / negative regulation of T-helper 17 cell lineage commitment / Interleukin-9 signaling ...negative regulation of dendritic cell cytokine production / : / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / tyrosine phosphorylation of STAT protein / negative regulation of T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / negative regulation of T cell activation / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / growth hormone receptor binding / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / regulation of receptor signaling pathway via JAK-STAT / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / extrinsic component of plasma membrane / Interleukin-20 family signaling / Signaling by ALK / negative regulation of interleukin-10 production / enzyme-linked receptor protein signaling pathway / T cell homeostasis / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / Interleukin-7 signaling / B cell differentiation / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / adaptive immune response / Potential therapeutics for SARS / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / innate immune response / ATP binding / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak3 / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain ...Tyrosine-protein kinase, non-receptor Jak3 / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / PH-like domain superfamily / 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-3C9 / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsKuglstatter, A. / Shao, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines
Authors: De Vicente, J. / Lemoine, R. / Bartlett, M. / Hermann, J.C. / Hekmat-Nejad, M. / Henningsen, R. / Jin, S. / Kuglstatter, A. / Li, H. / Lovey, A.J. / Menke, J. / Niu, L. / Patel, V. / ...Authors: De Vicente, J. / Lemoine, R. / Bartlett, M. / Hermann, J.C. / Hekmat-Nejad, M. / Henningsen, R. / Jin, S. / Kuglstatter, A. / Li, H. / Lovey, A.J. / Menke, J. / Niu, L. / Patel, V. / Petersen, A. / Setti, L. / Shao, A. / Tivitmahaisoon, P. / Vu, M.D. / Soth, M.
History
DepositionJul 7, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 27, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 8, 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 JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9942
Polymers35,6141
Non-polymers3801
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.921, 75.703, 89.729
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 JAK3 / Janus kinase 3 / JAK-3 / Leukocyte janus kinase / L-JAK


Mass: 35613.598 Da / Num. of mol.: 1 / Fragment: RESIDUES 811-1124, PROTEIN KINASE DOMAIN / Mutation: C1040S, C1048S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-3C9 / 1-{(3S)-1-[(2-methylpropyl)sulfonyl]piperidin-3-yl}-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)urea


Mass: 380.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H24N6O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 2.24 Å3/Da / Density % sol: 45.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 30% PEG 3350, 0.1M MES, 0.2M MgCl, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.4→44.86 Å / Num. obs: 11477 / % possible obs: 92.34 % / Redundancy: 5.1 % / Biso Wilson estimate: 37.34 Å2 / Rsym value: 0.078 / Net I/σ(I): 11.9
Reflection shellResolution: 2.4→2.5 Å / Redundancy: 1.7 % / Mean I/σ(I) obs: 1.82 / Num. unique all: 740 / Rsym value: 0.355 / % possible all: 52.4

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4HVD

4hvd


Resolution: 2.4→44.86 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.89 / SU B: 21.115 / SU ML: 0.248 / Cross valid method: THROUGHOUT / ESU R: 0.54 / ESU R Free: 0.308 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27256 571 4.7 %RANDOM
Rwork0.20696 ---
obs0.21009 11477 92.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.143 Å2
Baniso -1Baniso -2Baniso -3
1--0.55 Å2-0 Å2-0 Å2
2---0.02 Å20 Å2
3---0.57 Å2
Refinement stepCycle: LAST / Resolution: 2.4→44.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2221 0 26 82 2329
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192306
X-RAY DIFFRACTIONr_bond_other_d0.0010.022170
X-RAY DIFFRACTIONr_angle_refined_deg1.4091.9933120
X-RAY DIFFRACTIONr_angle_other_deg0.79434995
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.875274
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.76522.804107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.88315392
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.9411521
X-RAY DIFFRACTIONr_chiral_restr0.0770.2329
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212583
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02538
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_it1.6582.2511105
X-RAY DIFFRACTIONr_mcbond_other1.6552.2491104
X-RAY DIFFRACTIONr_mcangle_it2.8713.361376
X-RAY DIFFRACTIONr_mcangle_other2.8713.3631377
X-RAY DIFFRACTIONr_scbond_it1.8012.5351201
X-RAY DIFFRACTIONr_scbond_other1.8082.5411172
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.073.7111704
X-RAY DIFFRACTIONr_long_range_B_refined4.96118.0342599
X-RAY DIFFRACTIONr_long_range_B_other4.94117.9752549
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 16 -
Rwork0.284 438 -
obs--47.34 %
Refinement TLS params.Method: refined / Origin x: 3.0885 Å / Origin y: -13.8144 Å / Origin z: -14.7951 Å
111213212223313233
T0.1226 Å20.0082 Å20.004 Å2-0.0251 Å20.0184 Å2--0.0229 Å2
L0.3416 °2-0.0375 °2-0.2303 °2-0.62 °20.4916 °2--1.3506 °2
S0.0116 Å °-0.0073 Å °0.0105 Å °-0.0474 Å °0.0284 Å °-0.0483 Å °-0.001 Å °0.0294 Å °-0.0399 Å °

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