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- PDB-4k6z: The Jak1 kinase domain in complex with compound 37 -

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Basic information

Entry
Database: PDB / ID: 4k6z
TitleThe Jak1 kinase domain in complex with compound 37
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / type III interferon-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / 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 / type III interferon-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / 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 / interleukin-6-mediated signaling pathway / type I interferon-mediated signaling pathway / Interleukin-6 signaling / 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 / Evasion by RSV of host interferon responses / 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 / 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 / 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-1Q3 / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsFong, R. / Lupardus, P.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors.
Authors: Labadie, S. / Barrett, K. / Blair, W.S. / Chang, C. / Deshmukh, G. / Eigenbrot, C. / Gibbons, P. / Johnson, A. / Kenny, J.R. / Kohli, P.B. / Liimatta, M. / Lupardus, P.J. / Shia, S. / ...Authors: Labadie, S. / Barrett, K. / Blair, W.S. / Chang, C. / Deshmukh, G. / Eigenbrot, C. / Gibbons, P. / Johnson, A. / Kenny, J.R. / Kohli, P.B. / Liimatta, M. / Lupardus, P.J. / Shia, S. / Steffek, M. / Ubhayakar, S. / Abbema, A.V. / Zak, M.
History
DepositionApr 16, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2013Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0682
Polymers34,7471
Non-polymers3211
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)168.574, 42.701, 44.301
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 / Fragment: Jak1 kinase domain, UNP residues 854-1154
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-1Q3 / (1R,2S)-2-{[8-oxo-2-(1H-pyrazol-4-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-4-yl]amino}cyclopentanecarbonitrile


Mass: 321.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N7O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.29 Å3/Da / Density % sol: 46.39 %
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, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.977 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 2.73→84.29 Å / Num. obs: 8938 / % possible obs: 98.9 % / Redundancy: 6.9 % / Biso Wilson estimate: 55.63 Å2 / Rmerge(I) obs: 0.095
Reflection shellResolution: 2.73→2.88 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.495 / Mean I/σ(I) obs: 3.9 / Num. unique all: 1258 / % possible all: 98.1

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
BUSTER2.11.4refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.73→42.85 Å / Cor.coef. Fo:Fc: 0.8967 / Cor.coef. Fo:Fc free: 0.8228 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2971 884 9.93 %RANDOM
Rwork0.2381 ---
obs0.2438 8906 98.24 %-
Displacement parametersBiso mean: 52.97 Å2
Baniso -1Baniso -2Baniso -3
1-7.6521 Å20 Å20 Å2
2--2.8031 Å20 Å2
3----10.4552 Å2
Refine analyzeLuzzati coordinate error obs: 0.427 Å
Refinement stepCycle: LAST / Resolution: 2.73→42.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2291 0 24 28 2343
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012368HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.193194HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d844SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes60HARMONIC2
X-RAY DIFFRACTIONt_gen_planes352HARMONIC5
X-RAY DIFFRACTIONt_it2368HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.63
X-RAY DIFFRACTIONt_other_torsion20.97
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion292SEMIHARMONIC5
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_contact2739SEMIHARMONIC4
LS refinement shellResolution: 2.73→3.05 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.4007 246 10.11 %
Rwork0.3088 2187 -
all0.318 2433 -
obs--98.24 %

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