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- PDB-6dbk: Tyk2 with compound 8 -

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Basic information

Entry
Database: PDB / ID: 6dbk
TitleTyk2 with compound 8
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / kinase
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-35 Signalling ...type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / growth hormone receptor binding / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / Interleukin-10 signaling / MAPK1 (ERK2) activation / positive regulation of natural killer cell proliferation / cell surface receptor signaling pathway via JAK-STAT / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / non-specific protein-tyrosine kinase / positive regulation of receptor signaling pathway via JAK-STAT / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / cytoplasmic side of plasma membrane / cellular response to virus / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / Interferon alpha/beta signaling / positive regulation of type II interferon production / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / intracellular signal transduction / immune response / protein phosphorylation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / extracellular exosome / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase, non-receptor, TYK2, N-terminal / 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 superfamily, second domain / FERM domain ...Tyrosine-protein kinase, non-receptor, TYK2, N-terminal / 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 superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / 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-G5D / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
AuthorsVajdos, F.F.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8- ...Title: Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841).
Authors: Fensome, A. / Ambler, C.M. / Arnold, E. / Banker, M.E. / Brown, M.F. / Chrencik, J. / Clark, J.D. / Dowty, M.E. / Efremov, I.V. / Flick, A. / Gerstenberger, B.S. / Gopalsamy, A. / Hayward, M. ...Authors: Fensome, A. / Ambler, C.M. / Arnold, E. / Banker, M.E. / Brown, M.F. / Chrencik, J. / Clark, J.D. / Dowty, M.E. / Efremov, I.V. / Flick, A. / Gerstenberger, B.S. / Gopalsamy, A. / Hayward, M.M. / Hegen, M. / Hollingshead, B.D. / Jussif, J. / Knafels, J.D. / Limburg, D.C. / Lin, D. / Lin, T.H. / Pierce, B.S. / Saiah, E. / Sharma, R. / Symanowicz, P.T. / Telliez, J.B. / Trujillo, J.I. / Vajdos, F.F. / Vincent, F. / Wan, Z.K. / Xing, L. / Yang, X. / Yang, X. / Zhang, L.
History
DepositionMay 3, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 7, 2018Group: 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

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Assembly

Deposited unit
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9562
Polymers36,5511
Non-polymers4051
Water2,828157
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.483, 73.139, 103.026
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Non-receptor tyrosine-protein kinase TYK2


Mass: 36550.570 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: C936A, C1142A, Q969A, E971A, K972A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF21
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-G5D / 4-({4-[(1S,4S)-5-(cyanoacetyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-2-yl}amino)-N-ethylbenzamide


Mass: 405.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 157 / 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: 1.89 Å3/Da / Density % sol: 34.87 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1 M bis-tris pH 5.5, 0.25 M NaCl, 10 mM TCEP, 27-33% PEG-3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 19, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→103.026 Å / Num. obs: 19090 / % possible obs: 98.5 % / Redundancy: 5.7 % / Biso Wilson estimate: 35.38 Å2 / Rpim(I) all: 0.028 / Rrim(I) all: 0.07 / Rsym value: 0.059 / Net I/av σ(I): 9.1 / Net I/σ(I): 17.8 / Num. measured all: 108957
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
2-2.113.10.3362.326180.2360.4420.33694.9
2.11-2.235.20.3042.325710.1540.3620.30498.5
2.23-2.396.30.2582.624680.120.3010.25899
2.39-2.586.60.1733.823030.0770.20.17399.1
2.58-2.836.40.1195.621000.0540.1390.11998.9
2.83-3.166.50.0758.719520.0340.0880.07599.6
3.16-3.656.20.04912.517360.0230.0580.04999.3
3.65-4.476.20.03816.214630.0170.0440.03899.6
4.47-6.325.90.03517.711730.0160.0410.03599.1
6.32-103.0265.60.03316.67060.0160.0380.03399.4

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER2.11.2refinement
PDB_EXTRACT3.24data extraction
RefinementResolution: 2→59.64 Å / Cor.coef. Fo:Fc: 0.9426 / Cor.coef. Fo:Fc free: 0.9134 / SU R Cruickshank DPI: 0.216 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.23 / SU Rfree Blow DPI: 0.186 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.2489 970 5.1 %RANDOM
Rwork0.2006 ---
obs0.203 19007 98.25 %-
Displacement parametersBiso max: 132.33 Å2 / Biso mean: 42.07 Å2 / Biso min: 16.37 Å2
Baniso -1Baniso -2Baniso -3
1--0.5911 Å20 Å20 Å2
2--7.4132 Å20 Å2
3----6.8221 Å2
Refine analyzeLuzzati coordinate error obs: 0.255 Å
Refinement stepCycle: final / Resolution: 2→59.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2344 0 53 157 2554
Biso mean--35.19 47.11 -
Num. residues----290
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d847SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes55HARMONIC2
X-RAY DIFFRACTIONt_gen_planes378HARMONIC5
X-RAY DIFFRACTIONt_it2462HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
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_contact2895SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2462HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3359HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion19.61
LS refinement shellResolution: 2→2.11 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2486 134 5.12 %
Rwork0.2285 2485 -
all0.2295 2619 -
obs--98.25 %

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