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- PDB-6aak: Crystal structure of JAK3 in complex with peficitinib -

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Basic information

Entry
Database: PDB / ID: 6aak
TitleCrystal structure of JAK3 in complex with peficitinib
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE/INHIBITOR / protein kinase / 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-9T6 / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.67 Å
AuthorsAmano, Y.
CitationJournal: Bioorg. Med. Chem. / Year: 2018
Title: Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor
Authors: Hamaguchi, H. / Amano, Y. / Moritomo, A. / Shirakami, S. / Nakajima, Y. / Nakai, K. / Nomura, N. / Ito, M. / Higashi, Y. / Inoue, T.
History
DepositionJul 18, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 15, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 12, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed
Revision 1.2Oct 24, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK3
B: Tyrosine-protein kinase JAK3
C: Tyrosine-protein kinase JAK3
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,7398
Polymers131,4344
Non-polymers1,3064
Water1,27971
1
A: Tyrosine-protein kinase JAK3
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,3704
Polymers65,7172
Non-polymers6532
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Tyrosine-protein kinase JAK3
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,3704
Polymers65,7172
Non-polymers6532
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.076, 114.644, 107.358
Angle α, β, γ (deg.)90.00, 97.65, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Tyrosine-protein kinase JAK3 / Janus kinase 3 / JAK-3


Mass: 32858.430 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN, UNP residues 814-1100 / Mutation: C1040S, C1048S / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-9T6 / 4-[[(1S,3R)-5-oxidanyl-2-adamantyl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide


Mass: 326.393 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H22N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.72 Å3/Da / Density % sol: 54.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: buffer, salt, precipitant

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Feb 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.67→106.4 Å / Num. obs: 36956 / % possible obs: 94.8 % / Observed criterion σ(I): 0 / Redundancy: 2 % / Rmerge(I) obs: 0.063 / Net I/σ(I): 12.16
Reflection shellResolution: 2.67→2.92 Å / Redundancy: 2 % / Rmerge(I) obs: 0.437 / % possible all: 91.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.67→106.4 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.854 / SU B: 39.382 / SU ML: 0.382 / Cross valid method: THROUGHOUT / ESU R: 1.991 / ESU R Free: 0.403 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.326 822 2.2 %RANDOM
Rwork0.269 ---
obs0.269 36123 94.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 39.51 Å2
Baniso -1Baniso -2Baniso -3
1--2.22 Å20 Å2-0.22 Å2
2---2.68 Å20 Å2
3---4.84 Å2
Refinement stepCycle: LAST / Resolution: 2.67→106.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8665 0 96 71 8832
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0228984
X-RAY DIFFRACTIONr_bond_other_d0.0020.028147
X-RAY DIFFRACTIONr_angle_refined_deg1.2481.99912209
X-RAY DIFFRACTIONr_angle_other_deg0.957318841
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.93651094
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.66122.883392
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.964151443
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6921572
X-RAY DIFFRACTIONr_chiral_restr0.0680.21322
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.029928
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021890
X-RAY DIFFRACTIONr_nbd_refined0.1810.21718
X-RAY DIFFRACTIONr_nbd_other0.1380.27829
X-RAY DIFFRACTIONr_nbtor_refined0.1620.24308
X-RAY DIFFRACTIONr_nbtor_other0.0760.24762
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.2197
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1130.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1480.280
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0710.21
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.67427106
X-RAY DIFFRACTIONr_mcbond_other0.30422213
X-RAY DIFFRACTIONr_mcangle_it2.21938834
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.39244093
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.91363375
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.67→2.74 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.412 53 -
Rwork0.322 2220 -
obs--79.81 %

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