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- PDB-6nzf: CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN)... -

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Basic information

Entry
Database: PDB / ID: 6nzf
TitleCRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound_5 AKA 4-[(2-CARBAMOYLPHEN YL)AMINO]-6-[(5-FLUOROPYRIDIN-2-YL)AMINO]-N-METHYLPYRIDINE -3-CARBOXAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / JTK1
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-L91 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 Å
AuthorsMuckelbauer, J.M.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Identification ofN-Methyl Nicotinamide andN-Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2).
Authors: Moslin, R. / Zhang, Y. / Wrobleski, S.T. / Lin, S. / Mertzman, M. / Spergel, S. / Tokarski, J.S. / Strnad, J. / Gillooly, K. / McIntyre, K.W. / Zupa-Fernandez, A. / Cheng, L. / Sun, H. / ...Authors: Moslin, R. / Zhang, Y. / Wrobleski, S.T. / Lin, S. / Mertzman, M. / Spergel, S. / Tokarski, J.S. / Strnad, J. / Gillooly, K. / McIntyre, K.W. / Zupa-Fernandez, A. / Cheng, L. / Sun, H. / Chaudhry, C. / Huang, C. / D'Arienzo, C. / Heimrich, E. / Yang, X. / Muckelbauer, J.K. / Chang, C. / Tredup, J. / Mulligan, D. / Xie, D. / Aranibar, N. / Chiney, M. / Burke, J.R. / Lombardo, L. / Carter, P.H. / Weinstein, D.S.
History
DepositionFeb 13, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 24, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 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.title / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)72,1177
Polymers70,9982
Non-polymers1,1195
Water61334
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-35 kcal/mol
Surface area21370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.394, 66.100, 75.155
Angle α, β, γ (deg.)90.000, 112.890, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 35499.156 Da / Num. of mol.: 2 / Fragment: Pseudo kinase domain, residues 575-869
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Plasmid: pFastBac1 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-L91 / 6-[(5-fluoropyridin-2-yl)amino]-N-methyl-4-{[2-(methylsulfonyl)phenyl]amino}pyridine-3-carboxamide


Mass: 415.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18FN5O3S
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 34 / 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: 2.27 Å3/Da / Density % sol: 45.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 200 mM ammonium sulfate, and 100 mM HEPES buffer, pH 7.5, 30%(W/V) PEG 5000 (Methyl Ether)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 13, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.39→46.29 Å / Num. obs: 25218 / % possible obs: 99.2 % / Redundancy: 3.3 % / Biso Wilson estimate: 56.73 Å2 / Rsym value: 0.054 / Net I/σ(I): 13.4
Reflection shellResolution: 7.55→46.29 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 39.3 / Rsym value: 0.02 / % possible all: 97.3

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WOV

4wov


Resolution: 2.39→46.29 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.899 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.301 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.283 / SU Rfree Blow DPI: 0.207 / SU Rfree Cruickshank DPI: 0.214
RfactorNum. reflection% reflectionSelection details
Rfree0.231 1276 5.07 %RANDOM
Rwork0.203 ---
obs0.205 25176 99.1 %-
Displacement parametersBiso max: 125.85 Å2 / Biso mean: 51.05 Å2 / Biso min: 30.23 Å2
Baniso -1Baniso -2Baniso -3
1-4.215 Å20 Å2-5.2898 Å2
2---17.4172 Å20 Å2
3---13.2022 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.39→46.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3687 0 73 34 3794
Biso mean--48.46 47.28 -
Num. residues----495
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1225SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes64HARMONIC2
X-RAY DIFFRACTIONt_gen_planes644HARMONIC5
X-RAY DIFFRACTIONt_it3884HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion503SEMIHARMONIC5
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_contact4284SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3884HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5322HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion3.15
X-RAY DIFFRACTIONt_other_torsion16.82
LS refinement shellResolution: 2.39→2.49 Å / Rfactor Rfree error: 0 / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.269 162 5.62 %
Rwork0.221 2720 -
all0.224 2882 -
obs--99.93 %

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