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- PDB-3eyg: Crystal structures of JAK1 and JAK2 inhibitor complexes -

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Basic information

Entry
Database: PDB / ID: 3eyg
TitleCrystal structures of JAK1 and JAK2 inhibitor complexes
ComponentsTyrosine-protein kinase
KeywordsTRANSFERASE / JAK kinase / ATP-binding / Kinase / Nucleotide-binding / Phosphoprotein / SH2 domain / Tyrosine-protein kinase
Function / homology
Function and homology information


protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / 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 / positive regulation of homotypic cell-cell adhesion / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / 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 / Interleukin-6 signaling / type I interferon-mediated signaling pathway / 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 / response to antibiotic / protein phosphorylation / 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-MI1 / Tyrosine-protein kinase JAK1 / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.9 Å
AuthorsWilliams, N.K. / Bamert, R.S. / Patell, O. / Wang, C. / Walden, P.M. / Fantino, E.
CitationJournal: J.Mol.Biol. / Year: 2009
Title: Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.
Authors: Williams, N.K. / Bamert, R.S. / Patel, O. / Wang, C. / Walden, P.M. / Wilks, A.F. / Fantino, E. / Rossjohn, J. / Lucet, I.S.
History
DepositionOct 20, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8022
Polymers33,4891
Non-polymers3121
Water4,774265
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.025, 88.218, 145.834
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1229-

HOH

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Components

#1: Protein Tyrosine-protein kinase


Mass: 33489.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, hCG_22179 / Production host: Escherichia coli (E. coli)
References: UniProt: Q59GQ2, UniProt: P23458*PLUS, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-MI1 / 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile / CP-690,550 / Tofacitinib


Mass: 312.370 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H20N6O / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 265 / 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: 2.16 Å3/Da / Density % sol: 43.11 %

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.9→20.08 Å / Num. all: 26544 / Num. obs: 26544

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019refinement
PDB_EXTRACT3.006data extraction
RefinementResolution: 1.9→18.87 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.925 / Occupancy max: 1 / Occupancy min: 0.1 / SU B: 3.289 / SU ML: 0.096 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.153 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.214 1188 5.1 %RANDOM
Rwork0.169 ---
obs0.171 23336 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 70.88 Å2 / Biso mean: 22.673 Å2 / Biso min: 3.78 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20 Å20 Å2
2--0.65 Å20 Å2
3----0.72 Å2
Refinement stepCycle: LAST / Resolution: 1.9→18.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2297 0 23 265 2585
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222373
X-RAY DIFFRACTIONr_angle_refined_deg1.5351.9883202
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0175281
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.93224.167108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.14915436
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8191513
X-RAY DIFFRACTIONr_chiral_restr0.1020.2343
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021764
X-RAY DIFFRACTIONr_nbd_refined0.2060.21175
X-RAY DIFFRACTIONr_nbtor_refined0.3140.21626
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1740.2233
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1820.265
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2250.227
X-RAY DIFFRACTIONr_mcbond_it2.31831457
X-RAY DIFFRACTIONr_mcangle_it3.51652277
X-RAY DIFFRACTIONr_scbond_it5.79171059
X-RAY DIFFRACTIONr_scangle_it8.53310925
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 83 -
Rwork0.21 1603 -
all-1686 -
obs--100 %

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