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- PDB-6n7c: Structure of the human JAK1 kinase domain with compound 56 -

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Basic information

Entry
Database: PDB / ID: 6n7c
TitleStructure of the human JAK1 kinase domain with compound 56
ComponentsTyrosine-protein kinase JAK1
KeywordsIMMUNE SYSTEM / JAK1 / IL13 / IL-13 / JAK2 / JAK3 / TYK2
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / protein localization to cell-cell junction / interleukin-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway ...type III interferon-mediated signaling pathway / protein localization to cell-cell junction / interleukin-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / 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 / positive regulation of homotypic cell-cell adhesion / interleukin-2-mediated signaling pathway / interleukin-15-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / Interleukin-15 signaling / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / Other interleukin signaling / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / IFNG signaling activates MAPKs / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / positive regulation of sprouting angiogenesis / MAPK1 (ERK2) activation / Interleukin-10 signaling / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Interleukin receptor SHC signaling / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / Interleukin-7 signaling / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytokine-mediated signaling pathway / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / cellular response to virus / positive regulation of protein localization to nucleus / ISG15 antiviral mechanism / cytoplasmic side of plasma membrane / Interferon gamma signaling / Interferon alpha/beta signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / receptor complex / endosome / intracellular signal transduction / protein phosphorylation / response to antibiotic / 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 / : / 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 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 / : / SH2 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 / 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-KF1 / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.69 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
Revision 1.2Nov 6, 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 JAK1
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,3545
Polymers69,4932
Non-polymers8613
Water9,152508
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1312
Polymers34,7471
Non-polymers3841
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2233
Polymers34,7471
Non-polymers4762
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.030, 90.040, 174.310
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 JAK1 / Janus kinase 1 / JAK-1


Mass: 34746.594 Da / Num. of mol.: 2
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-KF1 / N-[5-(3-methoxynaphthalen-2-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 384.391 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H16N6O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 508 / 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: 2.43 Å3/Da / Density % sol: 49.37 %
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: 0.92 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 23, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.69→32.51 Å / Num. obs: 76148 / % possible obs: 99.1 % / Redundancy: 6.6 % / Biso Wilson estimate: 18.2 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.088 / Net I/σ(I): 11.9
Reflection shellResolution: 1.69→1.73 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.63 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 5550 / CC1/2: 0.883 / % possible all: 99.1

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 1.69→32.28 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.918 / SU R Cruickshank DPI: 0.128 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.135 / SU Rfree Blow DPI: 0.13 / SU Rfree Cruickshank DPI: 0.125
RfactorNum. reflection% reflectionSelection details
Rfree0.288 3729 4.9 %RANDOM
Rwork0.252 ---
obs0.254 76063 98.9 %-
Displacement parametersBiso mean: 19.81 Å2
Baniso -1Baniso -2Baniso -3
1-0.3488 Å20 Å20 Å2
2---1.0143 Å20 Å2
3---0.6655 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: 1 / Resolution: 1.69→32.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4376 0 128 508 5012
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014629HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.966251HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1626SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes829HARMONIC5
X-RAY DIFFRACTIONt_it4629HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion15.35
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion570SEMIHARMONIC5
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_contact5490SEMIHARMONIC4
LS refinement shellResolution: 1.69→1.73 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2372 244 4.41 %
Rwork0.2294 5294 -
all0.2298 5538 -
obs--99.09 %

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