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- PDB-3nyx: Non-phosphorylated TYK2 JH1 domain with Quinoline-Thiadiazole-Thi... -

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Basic information

Entry
Database: PDB / ID: 3nyx
TitleNon-phosphorylated TYK2 JH1 domain with Quinoline-Thiadiazole-Thiophene Inhibitor
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / tyrosine phosphorylation / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-27 signaling ...type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of natural killer cell proliferation / 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 / MAPK3 (ERK1) activation / positive regulation of interleukin-17 production / 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 / type II interferon-mediated signaling pathway / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / 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 / Evasion by RSV of host interferon responses / 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 / Signaling by ALK fusions and activated point mutants / 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 / cytoplasm / cytosol
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
2,3-DIHYDROXY-1,4-DITHIOBUTANE / Chem-TZ1 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsEigenbrot, C. / Ultsch, M.
CitationJournal: Proteins / Year: 2011
Title: A new regulatory switch in a JAK protein kinase.
Authors: Tsui, V. / Gibbons, P. / Ultsch, M. / Mortara, K. / Chang, C. / Blair, W. / Pulk, R. / Stanley, M. / Starovasnik, M. / Williams, D. / Lamers, M. / Leonard, P. / Magnuson, S. / Liang, J. / Eigenbrot, C.
History
DepositionJul 15, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 20, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)35,7154
Polymers35,0021
Non-polymers7133
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.318, 70.436, 86.488
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsThe asymmetric unit is one full biological assembly

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Components

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


Mass: 35002.059 Da / Num. of mol.: 1 / Fragment: kinase domain JH1 / Mutation: Asp1023Asn
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): sf9
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-TZ1 / N-{5-[(7-chloroquinolin-4-yl)sulfanyl]-1,3,4-thiadiazol-2-yl}thiophene-2-carboxamide


Mass: 404.917 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H9ClN4OS3
#3: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL


Mass: 154.251 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O2S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.41 Å3/Da / Density % sol: 48.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 0
Details: PEG3350, sodium acetate, pH 0.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 28, 2008
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. all: 12296 / Num. obs: 12234 / % possible obs: 99.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -2 / Redundancy: 4.4 % / Biso Wilson estimate: 42 Å2 / Rsym value: 0.137 / Net I/σ(I): 10

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3NZ0

3nz0


Resolution: 2.5→40 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.875 / SU B: 22.058 / SU ML: 0.258 / Cross valid method: THROUGHOUT / ESU R Free: 0.327 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27481 684 5.6 %RANDOM
Rwork0.21546 ---
all0.22 12234 --
obs0.21902 11450 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.222 Å2
Baniso -1Baniso -2Baniso -3
1-1.36 Å20 Å20 Å2
2---2.03 Å20 Å2
3---0.67 Å2
Refinement stepCycle: LAST / Resolution: 2.5→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 41 56 2449
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222498
X-RAY DIFFRACTIONr_angle_refined_deg1.5551.9813379
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0025292
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.3923120
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.02815431
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.6191519
X-RAY DIFFRACTIONr_chiral_restr0.0920.2354
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021913
X-RAY DIFFRACTIONr_nbd_refined0.210.21095
X-RAY DIFFRACTIONr_nbtor_refined0.3090.21642
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1330.278
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1880.254
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1020.28
X-RAY DIFFRACTIONr_mcbond_it3.4392.51490
X-RAY DIFFRACTIONr_mcangle_it5.29552351
X-RAY DIFFRACTIONr_scbond_it3.5272.51164
X-RAY DIFFRACTIONr_scangle_it5.1351028
LS refinement shellResolution: 2.5→2.635 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.392 104 -
Rwork0.306 1646 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 1.769 Å / Origin y: 6.1215 Å / Origin z: 13.1924 Å
111213212223313233
T-0.0049 Å2-0.0022 Å20.0096 Å2--0.048 Å20.0106 Å2---0.0134 Å2
L0.3166 °2-0.0675 °20.2009 °2-0.7552 °2-0.2605 °2--0.373 °2
S-0.0011 Å °-0.0006 Å °0.0265 Å °-0.0677 Å °-0.0258 Å °-0.0491 Å °0.037 Å °0.0063 Å °0.0268 Å °

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