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- PDB-6dbm: Tyk2 with compound 23 -

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Basic information

Entry
Database: PDB / ID: 6dbm
TitleTyk2 with compound 23
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 / type I interferon-mediated signaling pathway / Interleukin-6 signaling / 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-G4J / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.368 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)36,9402
Polymers36,5511
Non-polymers3891
Water1,802100
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.238, 73.317, 101.224
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-G4J / [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone


Mass: 389.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21F2N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 1.85 Å3/Da / Density % sol: 33.42 %
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: Jul 18, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.368→101.224 Å / Num. all: 10734 / Num. obs: 10734 / % possible obs: 92.9 % / Redundancy: 5.1 % / Rpim(I) all: 0.054 / Rrim(I) all: 0.126 / Rsym value: 0.103 / Net I/av σ(I): 5.8 / Net I/σ(I): 14.4 / Num. measured all: 54511
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.368-2.53.80.3212.4480612510.1970.4130.3213.276.9
2.5-2.654.20.2573564713340.1460.3230.2574.386.4
2.65-2.834.40.2033.7576113030.1170.2590.2035.788.3
2.83-3.064.70.155.1633613370.0870.1940.157.897.3
3.06-3.355.30.1295.6673312630.070.1610.12911.4100
3.35-3.745.70.1076660711590.0540.1290.10717.6100
3.74-4.326.20.0916.3653310490.0420.1060.09125.8100
4.32-5.296.10.0777.454338880.0350.0890.07730.2100
5.29-7.4960.0757.543247150.0350.0860.07528.9100
7.49-101.2245.40.03417.423314350.0170.040.03440.499.5

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
PHENIXrefinement
PDB_EXTRACT3.24data extraction
RefinementResolution: 2.368→50.612 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2643 544 5.09 %
Rwork0.201 10151 -
obs0.2042 10695 92.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 106.05 Å2 / Biso mean: 28.69 Å2 / Biso min: 6.32 Å2
Refinement stepCycle: final / Resolution: 2.368→50.612 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2227 0 28 100 2355
Biso mean--18.33 27.8 -
Num. residues----274
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022330
X-RAY DIFFRACTIONf_angle_d0.6413160
X-RAY DIFFRACTIONf_chiral_restr0.03336
X-RAY DIFFRACTIONf_plane_restr0.002409
X-RAY DIFFRACTIONf_dihedral_angle_d14.618882
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3677-2.6060.35321170.25422149226680
2.606-2.9830.28961210.24422423254490
2.983-3.75810.28761550.19627092864100
3.7581-50.62350.21351510.173328703021100

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