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- PDB-6n78: Structure of the human JAK1 kinase domain with compound 21 -

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Basic information

Entry
Database: PDB / ID: 6n78
TitleStructure of the human JAK1 kinase domain with compound 21
ComponentsTyrosine-protein kinase JAK1
KeywordsIMMUNE SYSTEM / JAK1 / IL13 / IL-13 / JAK2 / JAK3 / TYK2
Function / homology
Function and homology information


protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / type III interferon-mediated signaling pathway / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway ...protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / type III interferon-mediated signaling pathway / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / interleukin-15-mediated signaling pathway / Interleukin-15 signaling / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-2 signaling / growth hormone receptor binding / Other interleukin signaling / IFNG signaling activates MAPKs / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / positive regulation of sprouting angiogenesis / MAPK3 (ERK1) activation / Interleukin-10 signaling / MAPK1 (ERK2) activation / cell surface receptor signaling pathway via JAK-STAT / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-7 signaling / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / cytoplasmic side of plasma membrane / ISG15 antiviral mechanism / cellular response to virus / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / Interferon gamma signaling / Interferon alpha/beta signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / response to antibiotic / protein phosphorylation / focal adhesion / ubiquitin protein ligase binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak1 / 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 central domain / FERM superfamily, second domain ...Tyrosine-protein kinase, non-receptor Jak1 / 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 central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Src homology 2 (SH2) domain profile. / 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 / 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-KEP / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.83 Å
AuthorsLupardus, P.J. / Brown, D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.
Authors: Zak, M. / Hanan, E.J. / Lupardus, P. / Brown, D.G. / Robinson, C. / Siu, M. / Lyssikatos, J.P. / Romero, F.A. / Zhao, G. / Kellar, T. / Mendonca, R. / Ray, N.C. / Goodacre, S.C. / Crackett, ...Authors: Zak, M. / Hanan, E.J. / Lupardus, P. / Brown, D.G. / Robinson, C. / Siu, M. / Lyssikatos, J.P. / Romero, F.A. / Zhao, G. / Kellar, T. / Mendonca, R. / Ray, N.C. / Goodacre, S.C. / Crackett, P.H. / McLean, N. / Hurley, C.A. / Yuen, P.W. / Cheng, Y.X. / Liu, X. / Liimatta, M. / Kohli, P.B. / Nonomiya, J. / Salmon, G. / Buckley, G. / Lloyd, J. / Gibbons, P. / Ghilardi, N. / Kenny, J.R. / Johnson, A.
History
DepositionNov 27, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2019Provider: repository / Type: Initial release
Revision 1.1May 15, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2573
Polymers34,7471
Non-polymers5112
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, monomer in solution
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)171.910, 43.150, 45.450
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Tyrosine-protein kinase JAK1 / Janus kinase 1 / JAK-1


Mass: 34746.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-KEP / N-{3-[5-chloro-2-(difluoromethoxy)phenyl]-1-methyl-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 418.785 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H13ClF2N6O2
#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.: 146 / 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: 2.43 Å3/Da / Density % sol: 49.29 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M MES pH 5-6 and 25-35% PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9282 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 24, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9282 Å / Relative weight: 1
ReflectionResolution: 1.83→57.32 Å / Num. obs: 30830 / % possible obs: 100 % / Redundancy: 6.3 % / Biso Wilson estimate: 26.55 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.086 / Net I/σ(I): 8.8
Reflection shellResolution: 1.83→1.88 Å / Redundancy: 6 % / Rmerge(I) obs: 1.44 / Mean I/σ(I) obs: 1.1 / CC1/2: 0.665 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 1.83→45.45 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.908 / SU R Cruickshank DPI: 0.148 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.153 / SU Rfree Blow DPI: 0.138 / SU Rfree Cruickshank DPI: 0.136
RfactorNum. reflection% reflectionSelection details
Rfree0.261 1456 4.81 %RANDOM
Rwork0.234 ---
obs0.236 30261 98.3 %-
Displacement parametersBiso mean: 34.03 Å2
Baniso -1Baniso -2Baniso -3
1-10.714 Å20 Å20 Å2
2---9.7084 Å20 Å2
3----1.0056 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: 1 / Resolution: 1.83→45.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 67 146 2426
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012343HARMONIC2
X-RAY DIFFRACTIONt_angle_deg13162HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d825SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes413HARMONIC5
X-RAY DIFFRACTIONt_it2343HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.98
X-RAY DIFFRACTIONt_other_torsion17.02
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion287SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2572SEMIHARMONIC4
LS refinement shellResolution: 1.83→1.89 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3538 138 4.9 %
Rwork0.3106 2680 -
all0.3129 2818 -
obs--95.2 %

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