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- PDB-5khx: Crystal structure of JAK1 in complex with PF-4950736 -

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Basic information

Entry
Database: PDB / ID: 5khx
TitleCrystal structure of JAK1 in complex with PF-4950736
ComponentsTyrosine-protein kinase JAK1
Keywordstransferase/transferase INHIBITOR / JAK1 / Kinase / Inhibitor / Complex / transferase-transferase INHIBITOR complex
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-6TE / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.4 Å
AuthorsHan, S. / Caspers, N.L.
CitationJournal: Acta Crystallogr F Struct Biol Commun / Year: 2016
Title: Development of a high-throughput crystal structure-determination platform for JAK1 using a novel metal-chelator soaking system.
Authors: Caspers, N.L. / Han, S. / Rajamohan, F. / Hoth, L.R. / Geoghegan, K.F. / Subashi, T.A. / Vazquez, M.L. / Kaila, N. / Cronin, C.N. / Johnson, E. / Kurumbail, R.G.
History
DepositionJun 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2016Provider: repository / Type: Initial release
Revision 1.1May 16, 2018Group: Data collection / Database references / Derived calculations
Category: citation / citation_author / pdbx_struct_oper_list
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Oct 16, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7132
Polymers36,4171
Non-polymers2951
Water1,42379
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.250, 88.300, 146.840
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 36417.469 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-6TE / ~{N}-[3-[methyl(7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]methanesulfonamide


Mass: 295.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H17N5O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.06 Å3/Da / Density % sol: 40.24 %
Crystal growTemperature: 281 K / Method: vapor diffusion, hanging drop / Details: 30% PEG 1500, 8% MPD, 0.1 M Tris pH 9.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→73.42 Å / Num. obs: 26544 / Biso Wilson estimate: 48.42 Å2

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementResolution: 2.4→73.42 Å / Cor.coef. Fo:Fc: 0.9497 / Cor.coef. Fo:Fc free: 0.9056 / SU R Cruickshank DPI: 0.425 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.466 / SU Rfree Blow DPI: 0.263 / SU Rfree Cruickshank DPI: 0.262
RfactorNum. reflection% reflectionSelection details
Rfree0.2416 561 4.77 %RANDOM
Rwork0.1703 ---
obs0.1735 11773 96.83 %-
Displacement parametersBiso mean: 49.99 Å2
Baniso -1Baniso -2Baniso -3
1-7.7321 Å20 Å20 Å2
2---3.7005 Å20 Å2
3----4.0316 Å2
Refine analyzeLuzzati coordinate error obs: 0.258 Å
Refinement stepCycle: LAST / Resolution: 2.4→73.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2239 0 20 79 2338
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012358HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.183196HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d845SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes61HARMONIC2
X-RAY DIFFRACTIONt_gen_planes344HARMONIC5
X-RAY DIFFRACTIONt_it2358HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.75
X-RAY DIFFRACTIONt_other_torsion19.32
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion288SEMIHARMONIC5
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_contact2738SEMIHARMONIC4
LS refinement shellResolution: 2.4→2.63 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2343 125 4.77 %
Rwork0.188 2494 -
all0.1902 2619 -
obs--91.46 %
Refinement TLS params.Method: refined / Origin x: 10.4013 Å / Origin y: 3.9241 Å / Origin z: -16.6404 Å
111213212223313233
T-0.3822 Å2-0.024 Å2-0.0376 Å2--0.382 Å20.0234 Å2---0.3405 Å2
L2.9182 °20.1228 °20.6707 °2-1.6419 °20.9925 °2--2.0479 °2
S-0.048 Å °0.0826 Å °0.1767 Å °-0.0267 Å °0.0445 Å °0.0049 Å °-0.0705 Å °0.1484 Å °0.0035 Å °
Refinement TLS groupSelection details: { A|* }

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