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- PDB-5wo4: JAK1 complexed with compound 28 -

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Basic information

Entry
Database: PDB / ID: 5wo4
TitleJAK1 complexed with compound 28
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE / Protein tyrosine kinase
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-B7V / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.84 Å
AuthorsLesburg, C.A. / Patel, S.B.
CitationJournal: J. Med. Chem. / Year: 2017
Title: The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective ...Title: The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties.
Authors: Siu, T. / Brubaker, J. / Fuller, P. / Torres, L. / Zeng, H. / Close, J. / Mampreian, D.M. / Shi, F. / Liu, D. / Fradera, X. / Johnson, K. / Bays, N. / Kadic, E. / He, F. / Goldenblatt, P. / ...Authors: Siu, T. / Brubaker, J. / Fuller, P. / Torres, L. / Zeng, H. / Close, J. / Mampreian, D.M. / Shi, F. / Liu, D. / Fradera, X. / Johnson, K. / Bays, N. / Kadic, E. / He, F. / Goldenblatt, P. / Shaffer, L. / Patel, S.B. / Lesburg, C.A. / Alpert, C. / Dorosh, L. / Deshmukh, S.V. / Yu, H. / Klappenbach, J. / Elwood, F. / Dinsmore, C.J. / Fernandez, R. / Moy, L. / Young, J.R.
History
DepositionAug 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2017Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.name
Revision 1.2Dec 27, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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)70,2454
Polymers69,4932
Non-polymers7522
Water8,485471
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1222
Polymers34,7471
Non-polymers3761
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1222
Polymers34,7471
Non-polymers3761
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.570, 173.360, 44.650
Angle α, β, γ (deg.)90.00, 93.94, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 34746.594 Da / Num. of mol.: 2 / Fragment: UNP residues 854-1154
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B / Production host: unidentified baculovirus
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-B7V / 3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide


Mass: 375.810 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C17H18ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 471 / 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: 2.33 Å3/Da / Density % sol: 47.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 100 mM MES pH 6.0, 30% (w/v) PEG 6000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Sep 30, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.84→173 Å / Num. obs: 55407 / % possible obs: 99.5 % / Redundancy: 3.7 % / Biso Wilson estimate: 29.37 Å2 / Rmerge(I) obs: 0.071 / Net I/σ(I): 11.3
Reflection shellResolution: 1.84→1.846 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.545 / Num. unique obs: 548 / % possible all: 99.8

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
autoPROCdata scaling
autoBUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.84→26.94 Å / Cor.coef. Fo:Fc: 0.9529 / Cor.coef. Fo:Fc free: 0.941 / SU R Cruickshank DPI: 0.133 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.136 / SU Rfree Blow DPI: 0.12 / SU Rfree Cruickshank DPI: 0.119
RfactorNum. reflection% reflectionSelection details
Rfree0.2108 2505 4.53 %RANDOM
Rwork0.1865 ---
obs0.1876 55350 99.43 %-
Displacement parametersBiso mean: 35.14 Å2
Baniso -1Baniso -2Baniso -3
1-0.7441 Å20 Å20.785 Å2
2--0.0703 Å20 Å2
3----0.8144 Å2
Refine analyzeLuzzati coordinate error obs: 0.211 Å
Refinement stepCycle: 1 / Resolution: 1.84→26.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4636 0 52 471 5159
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014859HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.016556HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1740SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes126HARMONIC2
X-RAY DIFFRACTIONt_gen_planes711HARMONIC5
X-RAY DIFFRACTIONt_it4859HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.33
X-RAY DIFFRACTIONt_other_torsion16.87
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion597SEMIHARMONIC5
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_contact6021SEMIHARMONIC4
LS refinement shellResolution: 1.84→1.89 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2371 171 4.24 %
Rwork0.2052 3860 -
all0.2066 4031 -
obs--99.43 %

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