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- PDB-6sm8: Human jak1 kinase domain in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 6sm8
TitleHuman jak1 kinase domain in complex with inhibitor
Components(Tyrosine-protein kinase JAK1) x 2
KeywordsTRANSFERASE / Janus Kinase 1 kinase domain (JAK1)
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 / 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-LKT / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsRead, J.A. / Steuber, H.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.
Authors: Su, Q. / Banks, E. / Bebernitz, G. / Bell, K. / Borenstein, C.F. / Chen, H. / Chuaqui, C.E. / Deng, N. / Ferguson, A.D. / Kawatkar, S. / Grimster, N.P. / Ruston, L. / Lyne, P.D. / Read, J.A. ...Authors: Su, Q. / Banks, E. / Bebernitz, G. / Bell, K. / Borenstein, C.F. / Chen, H. / Chuaqui, C.E. / Deng, N. / Ferguson, A.D. / Kawatkar, S. / Grimster, N.P. / Ruston, L. / Lyne, P.D. / Read, J.A. / Peng, X. / Pei, X. / Fawell, S. / Tang, Z. / Throner, S. / Vasbinder, M.M. / Wang, H. / Winter-Holt, J. / Woessner, R. / Wu, A. / Yang, W. / Zinda, M. / Kettle, J.G.
History
DepositionAug 21, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 13, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 27, 2020Group: 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)70,4466
Polymers69,4362
Non-polymers1,0104
Water4,576254
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1892
Polymers34,7471
Non-polymers4431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2574
Polymers34,6901
Non-polymers5673
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.194, 174.065, 44.956
Angle α, β, γ (deg.)90.000, 94.160, 90.000
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.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Details: Human Jak1 Kinase domain / Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B / Production host: Escherichia coli (E. coli)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Protein Tyrosine-protein kinase JAK1 / Janus kinase 1 / JAK-1


Mass: 34689.543 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B / Production host: Escherichia coli (E. coli)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#3: Chemical ChemComp-LKT / 2-chloranyl-6-[(3~{S})-3-[(1~{S})-2-cyano-1-[4-(7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]ethyl]pyrrolidin-1-yl]benzenecarbonitrile


Mass: 442.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H19ClN8 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 254 / 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: 2.48 Å3/Da / Density % sol: 50.45 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 27% (m/v) PEG6000, 0.1 M MES/NaOH pH 6.0 and 5 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 1.85→87.04 Å / Num. obs: 56206 / % possible obs: 99.8 % / Redundancy: 4.2 % / Biso Wilson estimate: 28.49 Å2 / Rmerge(I) obs: 0.046 / Net I/σ(I): 18.76
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.448 / Num. unique obs: 8095 / % possible all: 99.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.85→35.48 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.926 / SU R Cruickshank DPI: 0.15 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.147 / SU Rfree Blow DPI: 0.133 / SU Rfree Cruickshank DPI: 0.135
RfactorNum. reflection% reflectionSelection details
Rfree0.241 2477 4.42 %RANDOM
Rwork0.212 ---
obs0.213 56072 99.8 %-
Displacement parametersBiso max: 162.14 Å2 / Biso mean: 45.01 Å2 / Biso min: 11.27 Å2
Baniso -1Baniso -2Baniso -3
1--0.1333 Å20 Å2-0.1992 Å2
2--3.0387 Å20 Å2
3----2.9054 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 1.85→35.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4717 0 72 255 5044
Biso mean--26.27 37.45 -
Num. residues----581
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1815SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes841HARMONIC5
X-RAY DIFFRACTIONt_it5041HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion620SEMIHARMONIC5
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_contact5932SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5041HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6818HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion3.22
X-RAY DIFFRACTIONt_other_torsion17.11
LS refinement shellResolution: 1.85→1.86 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3434 55 4.9 %
Rwork0.2662 1067 -
all0.2697 1122 -
obs--97.72 %
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)
13.4096-1.60112.71351.2077-1.6714.18450.30090.4065-0.9029-0.26310.14610.46070.14330.1844-0.4470.1412-0.03240.00660.2322-0.14090.4714-3.88758.737-2.494
26.5681-0.21041.38613.3445-0.7331.51090.0549-0.2164-1.37770.44530.18370.2046-0.0614-0.0303-0.23860.1414-0.0210.07520.11320.01470.438312.7651.58716.472
34.1951-0.0707-1.82821.8181-0.38553.4075-0.00610.19190.0196-0.36550.0374-0.2193-0.00010.0175-0.03130.131-0.02130.03270.1688-0.00590.081725.4693.203-2.898
48.30433.428-2.0123.8016-0.49861.37960.6853-1.19871.43670.4995-0.36610.8119-0.21880.3142-0.31920.1257-0.10370.13860.29-0.19780.27299.03110.1716.137
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|867 - A|959 }A867 - 959
2X-RAY DIFFRACTION2{ A|961 - A|1154 }A961 - 1154
3X-RAY DIFFRACTION3{ B|867 - B|959 }B867 - 959
4X-RAY DIFFRACTION4{ B|961 - B|1154 }B961 - 1154

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