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- PDB-6w8l: Crystal structure of JAK1 kinase with compound 10 -

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Basic information

Entry
Database: PDB / ID: 6w8l
TitleCrystal structure of JAK1 kinase with compound 10
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE/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 / 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 / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-R4S / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsVajdos, F.F.
CitationJournal: Bioorg.Med.Chem. / Year: 2020
Title: Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1.
Authors: Fensome, A. / Ambler, C.M. / Arnold, E. / Banker, M.E. / Clark, J.D. / Dowty, M.E. / Efremov, I.V. / Flick, A. / Gerstenberger, B.S. / Gifford, R.S. / Gopalsamy, A. / Hegen, M. / Jussif, J. ...Authors: Fensome, A. / Ambler, C.M. / Arnold, E. / Banker, M.E. / Clark, J.D. / Dowty, M.E. / Efremov, I.V. / Flick, A. / Gerstenberger, B.S. / Gifford, R.S. / Gopalsamy, A. / Hegen, M. / Jussif, J. / Limburg, D.C. / Lin, T.H. / Pierce, B.S. / Sharma, R. / Trujillo, J.I. / Vajdos, F.F. / Vincent, F. / Wan, Z.K. / Xing, L. / Yang, X. / Yang, X.
History
DepositionMar 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 29, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8052
Polymers36,4171
Non-polymers3871
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.920, 88.830, 146.760
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-R4S / N-[(1S,5R)-3-(5-fluoro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]cyclopropanecarboxamide


Mass: 387.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H22FN7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 40.14 %
Crystal growTemperature: 298 K / Method: evaporation / pH: 8 / Details: 0.1 M Tris pH 8.5, 6-9% MPD, 24-29% PEG-1500

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 27, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.11→73.38 Å / Num. obs: 17476 / % possible obs: 98.7 % / Redundancy: 6.4 % / Biso Wilson estimate: 42.14 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.049 / Rrim(I) all: 0.121 / Net I/σ(I): 10.2 / Num. measured all: 111413
Reflection shell

Num. unique obs: 874 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.11-2.1486.51.0156630.6520.4221.0971.798.8
5.933-73.385.70.0650150.9960.0290.06722.599.3

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DBN

6dbn


Resolution: 2.11→73.38 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.224 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.221 / SU Rfree Blow DPI: 0.173 / SU Rfree Cruickshank DPI: 0.175
RfactorNum. reflection% reflectionSelection details
Rfree0.226 885 5.06 %RANDOM
Rwork0.196 ---
obs0.197 17475 98.6 %-
Displacement parametersBiso max: 123.85 Å2 / Biso mean: 46.18 Å2 / Biso min: 20.83 Å2
Baniso -1Baniso -2Baniso -3
1--0.7539 Å20 Å20 Å2
2--1.7363 Å20 Å2
3----0.9824 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.11→73.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2281 0 28 32 2341
Biso mean--36.28 36.35 -
Num. residues----280
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d852SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes411HARMONIC5
X-RAY DIFFRACTIONt_it2384HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion291SEMIHARMONIC5
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_contact2644SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2384HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3239HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion18.17
LS refinement shellResolution: 2.11→2.24 Å / Rfactor Rfree error: 0 / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2169 168 6.01 %
Rwork0.2095 2627 -
all0.21 2795 -
obs--99.11 %
Refinement TLS params.Method: refined / Origin x: 10.4202 Å / Origin y: 4.3892 Å / Origin z: -16.844 Å
111213212223313233
T-0.1885 Å20.0158 Å2-0.0253 Å2--0.1487 Å20.0206 Å2---0.1834 Å2
L2.1041 °20.2884 °20.39 °2-2.061 °20.7541 °2--1.3519 °2
S-0.0655 Å °0.1757 Å °0.2168 Å °-0.0624 Å °-0.0133 Å °0.0394 Å °-0.062 Å °0.0772 Å °0.0788 Å °
Refinement TLS groupSelection details: { A|* }

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