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- PDB-6hzu: HUMAN JAK1 IN COMPLEX WITH LASW1393 -

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Basic information

Entry
Database: PDB / ID: 6hzu
TitleHUMAN JAK1 IN COMPLEX WITH LASW1393
ComponentsTyrosine-protein kinase JAK1
KeywordsPROTEIN BINDING / JANUS KINASE / JAK1 / KINASE DOMAIN / Proteros Biostructures GMBH
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-GYQ / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsLozoya, E. / Segarra, V. / Bach, J. / Jestel, A. / Lammens, A. / Blaesse, M.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases.
Authors: Bach, J. / Eastwood, P. / Gonzalez, J. / Gomez, E. / Alonso, J.A. / Fonquerna, S. / Lozoya, E. / Orellana, A. / Maldonado, M. / Calaf, E. / Alberti, J. / Perez, J. / Andres, A. / Prats, N. / ...Authors: Bach, J. / Eastwood, P. / Gonzalez, J. / Gomez, E. / Alonso, J.A. / Fonquerna, S. / Lozoya, E. / Orellana, A. / Maldonado, M. / Calaf, E. / Alberti, J. / Perez, J. / Andres, A. / Prats, N. / Carreno, C. / Calama, E. / De Alba, J. / Calbet, M. / Miralpeix, M. / Ramis, I.
History
DepositionOct 24, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Structure summary / Category: audit_author / struct_keywords
Item: _struct_keywords.pdbx_keywords / _struct_keywords.text
Revision 1.2Nov 6, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)70,2204
Polymers69,4932
Non-polymers7272
Water5,765320
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1102
Polymers34,7471
Non-polymers3631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1102
Polymers34,7471
Non-polymers3631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.794, 173.763, 44.864
Angle α, β, γ (deg.)90.00, 94.24, 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: KINASE DOMAIN / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-GYQ / 2-[4-[8-oxidanylidene-2-[(~{E})-(2-oxidanylidenepyridin-3-ylidene)amino]-7~{H}-purin-9-yl]cyclohexyl]ethanenitrile


Mass: 363.373 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17N7O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 320 / 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: 2.45 Å3/Da / Density % sol: 49.79 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 30 % PEG6000_50 0.10 M MES pH 6.00

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 13, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→87.04 Å / Num. obs: 32613 / % possible obs: 98.7 % / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Rrim(I) all: 0.1 / Rsym value: 0.088 / Net I/σ(I): 14
Reflection shellResolution: 2.2→2.37 Å / Redundancy: 4 % / Rmerge(I) obs: 0.446 / % possible all: 98.4

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.5.0109refinement
REFMAC5.5.0109phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→87.04 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.89 / SU B: 15.76 / SU ML: 0.184 / Cross valid method: THROUGHOUT / ESU R: 0.301 / ESU R Free: 0.239 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26545 1515 4.6 %RANDOM
Rwork0.20058 ---
obs0.20359 31098 98.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso mean: 28.682 Å2
Baniso -1Baniso -2Baniso -3
1--1 Å20 Å20.49 Å2
2---1.46 Å20 Å2
3---2.53 Å2
Refinement stepCycle: LAST / Resolution: 2.2→87.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4702 0 54 320 5076
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224773
X-RAY DIFFRACTIONr_bond_other_d0.0020.023337
X-RAY DIFFRACTIONr_angle_refined_deg1.2711.9896465
X-RAY DIFFRACTIONr_angle_other_deg2.2238083
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1255580
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.47324.481212
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.26115828
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0971524
X-RAY DIFFRACTIONr_chiral_restr0.0720.2695
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215295
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02939
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.75122901
X-RAY DIFFRACTIONr_mcbond_other0.30621170
X-RAY DIFFRACTIONr_mcangle_it2.82234681
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.88541872
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.35861784
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 103 -
Rwork0.246 2320 -
obs--97.78 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.1495-0.36491.59011.2367-1.19885.90330.03450.0978-0.352-0.23940.05790.15230.3534-0.1118-0.0923-0.1383-0.0126-0.0407-0.1193-0.0327-0.0929-2.83259.113-1.982
23.79180.15430.54522.0808-0.24651.71120.0282-0.1718-0.58330.14220.0604-0.04840.1099-0.0083-0.0887-0.12470.0019-0.0196-0.11620.0098-0.103513.13651.35216.505
33.579-0.2555-0.79091.9367-0.00235.80410.02110.1630.1879-0.3397-0.0026-0.1902-0.18460.1925-0.0186-0.12130.00360.0215-0.09440.0034-0.177624.3952.741-2.508
44.48140.9174-0.81173.1240.06491.92920.1433-0.31170.66260.1901-0.01450.3106-0.15990.0454-0.1289-0.10990.00260.0309-0.1052-0.036-0.15738.16210.00415.912
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A867 - 959
2X-RAY DIFFRACTION2A961 - 2000
3X-RAY DIFFRACTION3B867 - 959
4X-RAY DIFFRACTION4B961 - 2000

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