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- PDB-3zep: Crystal Structure of JAK3 Kinase Domain in Complex with a Pyrrolo... -

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Basic information

Entry
Database: PDB / ID: 3zep
TitleCrystal Structure of JAK3 Kinase Domain in Complex with a Pyrrolopyrazine-2-phenyl Ether Inhibitor
ComponentsTYROSINE-PROTEIN KINASE JAK3
KeywordsTRANSFERASE / STAT5 / STAT6 / INTERLEUKIN-2 / COMMON-GAMMA CHAIN / ATP SITE KINASE INHIBITOR / CANCER / SCID / SEVERE COMBINED IMMUNODEFICIENCY
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine production / negative regulation of FasL 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 / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling ...negative regulation of dendritic cell cytokine production / negative regulation of FasL 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 / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / tyrosine phosphorylation of STAT protein / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / Interleukin-2 signaling / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / extrinsic component of plasma membrane / Signaling by ALK / negative regulation of interleukin-10 production / Interleukin-20 family signaling / enzyme-linked receptor protein signaling pathway / T cell homeostasis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-7 signaling / B cell differentiation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / RAF/MAP kinase cascade / regulation of apoptotic process / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / adaptive immune response / Potential therapeutics for SARS / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / protein phosphorylation / 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 / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM domain / FERM domain profile. ...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 / 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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-1NX / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsKuglstatter, A. / Jestel, A. / Nagel, S. / Boettcher, J. / Blaesse, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of a Series of Novel 5H-Pyrrolo[2,3-B]Pyrazine-2-Phenyl Ethers, as Potent Jak3 Kinase Inhibitors.
Authors: Jaime-Figueroa, S. / De Vicente, J. / Hermann, J. / Jahangir, A. / Jin, S. / Kuglstatter, A. / Lynch, S.M. / Menke, J. / Niu, L. / Patel, V. / Shao, A. / Soth, M. / Vu, M.D. / Yee, C.
History
DepositionDec 6, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2016Group: Database references

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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)133,6649
Polymers131,8944
Non-polymers1,7705
Water5,026279
1
A: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3932
Polymers32,9741
Non-polymers4191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3932
Polymers32,9741
Non-polymers4191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4853
Polymers32,9741
Non-polymers5122
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3932
Polymers32,9741
Non-polymers4191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.554, 114.076, 104.196
Angle α, β, γ (deg.)90.00, 96.82, 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 / LEUKOCYTE JANUS KINASE / L-JAK


Mass: 32973.516 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN, RESIDUES 813-1100 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P52333, non-specific protein-tyrosine kinase, EC: 2.7.1.112
#2: Chemical
ChemComp-1NX / 2-[[(3R)-3-acetamido-2,3-dihydro-1H-inden-5-yl]oxy]-N-[(1S)-1-cyclopropylethyl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide


Mass: 419.476 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H25N5O3
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 279 / 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: 2.65 Å3/Da / Density % sol: 53.58 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 16, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.35→103.69 Å / Num. obs: 55677 / % possible obs: 97.1 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 6.9
Reflection shellResolution: 2.35→2.54 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 1.7 / % possible all: 94.3

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
REFMACRIGID BODYphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.35→103.7 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.879 / SU B: 19.145 / SU ML: 0.219 / Cross valid method: THROUGHOUT / ESU R: 0.4 / ESU R Free: 0.263 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED. DISORDERED SIDE CHAINS HAVE OCCUPANCY 0.00
RfactorNum. reflection% reflectionSelection details
Rfree0.26484 924 1.7 %RANDOM
Rwork0.22559 ---
obs0.22627 52795 96.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 41.076 Å2
Baniso -1Baniso -2Baniso -3
1--2.55 Å20 Å20.66 Å2
2---2.15 Å20 Å2
3---4.85 Å2
Refinement stepCycle: LAST / Resolution: 2.35→103.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8839 0 130 279 9248
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0199000
X-RAY DIFFRACTIONr_bond_other_d0.0010.026345
X-RAY DIFFRACTIONr_angle_refined_deg1.0982.01312201
X-RAY DIFFRACTIONr_angle_other_deg0.981315267
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.07851084
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.63122.853382
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.645151467
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9591575
X-RAY DIFFRACTIONr_chiral_restr0.0570.21318
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219885
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021902
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2.353→2.414 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.382 64 -
Rwork0.29 3527 -
obs--88.97 %
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)
12.2597-0.3515-0.64325.18791.30752.4571-0.01390.03970.5239-0.33750.1291-0.5781-0.11310.1524-0.1153-0.0842-0.01720.0127-0.04460.0196-0.1062-3.281-8.343-0.117
21.8693-0.1513-0.12122.9489-0.54433.08240.0111-0.1723-0.01210.25460.0498-0.15120.07160.0075-0.0608-0.0936-0.0252-0.0192-0.0449-0.0062-0.1937-15.012-25.29514.428
31.85681.95830.72448.7727-0.13910.9865-0.042-0.0445-0.35780.24990.0218-0.9276-0.02840.20630.0201-0.083-0.0025-0.0439-0.0732-0.0007-0.037819.83727.60456.575
41.4342-0.01140.99123.3973-0.14333.12370.03920.285-0.0109-0.2855-0.0462-0.1859-0.03610.19370.0069-0.09270.02330.0024-0.0476-0.005-0.09896.41640.24338.771
51.27330.9323-0.20226.28370.90031.23170.0301-0.1690.39420.2058-0.10430.86910.0772-0.32410.0742-0.0828-0.00240.0393-0.035-0.0229-0.0252-3.3728.56456.496
61.2912-0.40140.36932.68760.68853.02230.02870.2986-0.0869-0.3328-0.02020.2150.0056-0.0075-0.0084-0.05680.0488-0.0326-0.0339-0.025-0.11449.799-3.55937.865
72.30590.07070.67097.6711.48972.1033-0.0977-0.0036-0.52330.39690.1286-0.85260.06050.2128-0.0309-0.0607-0.0056-0.0322-0.0319-0.005-0.099125.68-47.1640.287
81.97010.11250.5733.30740.20722.4520.03790.20060.1353-0.38340.0376-0.2859-0.10420.1196-0.0754-0.04960.03060.0139-0.02570.0118-0.190613.415-30.323-13.828
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A814 - 904
2X-RAY DIFFRACTION2A905 - 1098
3X-RAY DIFFRACTION3B814 - 904
4X-RAY DIFFRACTION4B905 - 1100
5X-RAY DIFFRACTION5C814 - 904
6X-RAY DIFFRACTION6C905 - 1100
7X-RAY DIFFRACTION7D814 - 904
8X-RAY DIFFRACTION8D905 - 1099

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