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- PDB-6bbu: Crystal Structure of JAK1 in complex with compound 25 -

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Basic information

Entry
Database: PDB / ID: 6bbu
TitleCrystal Structure of JAK1 in complex with compound 25
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / TRANSFERASE / 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 / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / 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 / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-10-mediated signaling pathway / interleukin-2-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / interleukin-15-mediated signaling pathway / Interleukin-15 signaling / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / Other interleukin signaling / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / type I interferon-mediated signaling pathway / interleukin-6-mediated signaling pathway / MAPK3 (ERK1) activation / positive regulation of sprouting angiogenesis / MAPK1 (ERK2) activation / Interleukin-10 signaling / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / Interleukin-7 signaling / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / cellular response to virus / ISG15 antiviral mechanism / positive regulation of protein localization to nucleus / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Interferon gamma signaling / Interferon alpha/beta signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / protein phosphatase binding / Potential therapeutics for SARS / cell differentiation / cytoskeleton / protein phosphorylation / receptor complex / endosome / intracellular signal transduction / 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 / cytoplasm / cytosol
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 / SH2 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 / SH2 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-D7D / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.08 Å
AuthorsHan, S.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.
Authors: Vazquez, M.L. / Kaila, N. / Strohbach, J.W. / Trzupek, J.D. / Brown, M.F. / Flanagan, M.E. / Mitton-Fry, M.J. / Johnson, T.A. / TenBrink, R.E. / Arnold, E.P. / Basak, A. / Heasley, S.E. / ...Authors: Vazquez, M.L. / Kaila, N. / Strohbach, J.W. / Trzupek, J.D. / Brown, M.F. / Flanagan, M.E. / Mitton-Fry, M.J. / Johnson, T.A. / TenBrink, R.E. / Arnold, E.P. / Basak, A. / Heasley, S.E. / Kwon, S. / Langille, J. / Parikh, M.D. / Griffin, S.H. / Casavant, J.M. / Duclos, B.A. / Fenwick, A.E. / Harris, T.M. / Han, S. / Caspers, N. / Dowty, M.E. / Yang, X. / Banker, M.E. / Hegen, M. / Symanowicz, P.T. / Li, L. / Wang, L. / Lin, T.H. / Jussif, J. / Clark, J.D. / Telliez, J.B. / Robinson, R.P. / Unwalla, R.
History
DepositionOct 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
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)36,7412
Polymers36,4171
Non-polymers3231
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.530, 88.100, 146.050
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 / Fragment: Protein kinase 2, residues 841-1154
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-D7D / N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide


Mass: 323.414 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H21N5O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 2.05 Å3/Da / Density % sol: 40.15 %
Crystal growTemperature: 281 K / Method: vapor diffusion, hanging drop
Details: 250mM NaCl, 5mM TCEP, 10 mM ATP, 10 mM MgCl2, 30% PEG1500, 8% MPD, 0.1M 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: Oct 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.08→44.2 Å / Num. obs: 77218 / % possible obs: 89.8 % / Redundancy: 2 % / Biso Wilson estimate: 35.91 Å2 / Net I/σ(I): 14.4

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
XSCALEdata scaling
BUSTERphasing
RefinementResolution: 2.08→42.17 Å / Cor.coef. Fo:Fc: 0.9536 / Cor.coef. Fo:Fc free: 0.9423 / SU R Cruickshank DPI: 0.191 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.199 / SU Rfree Blow DPI: 0.158 / SU Rfree Cruickshank DPI: 0.156
RfactorNum. reflection% reflectionSelection details
Rfree0.2135 1035 5.37 %RANDOM
Rwork0.1829 ---
obs0.1846 19266 99.79 %-
Displacement parametersBiso mean: 44.45 Å2
Baniso -1Baniso -2Baniso -3
1-1.7809 Å20 Å20 Å2
2--1.4547 Å20 Å2
3----3.2356 Å2
Refine analyzeLuzzati coordinate error obs: 0.235 Å
Refinement stepCycle: 1 / Resolution: 2.08→42.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2271 0 22 127 2420
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012402HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043261HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d855SINUSOIDAL2
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_it2402HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion18.43
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_contact2694SEMIHARMONIC4
LS refinement shellResolution: 2.05→2.16 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2369 141 5.08 %
Rwork0.2003 2634 -
all0.2021 2775 -
obs--99.53 %
Refinement TLS params.Method: refined / Origin x: 10.692 Å / Origin y: 5.7382 Å / Origin z: -16.8746 Å
111213212223313233
T-0.0856 Å2-0.0084 Å2-0.0301 Å2--0.0668 Å20.0238 Å2---0.1313 Å2
L1.9528 °2-0.2293 °20.1784 °2-2.0297 °20.6926 °2--1.2927 °2
S0.0027 Å °0.1301 Å °0.0383 Å °-0.1763 Å °0.0003 Å °0.0868 Å °-0.0483 Å °0.0804 Å °-0.003 Å °
Refinement TLS groupSelection details: { A|* }

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