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- PDB-4gfo: TYK2 kinase (JH1 domain) with 2,6-DICHLORO-N-(2-OXO-2,5-DIHYDROPY... -

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Basic information

Entry
Database: PDB / ID: 4gfo
TitleTYK2 kinase (JH1 domain) with 2,6-DICHLORO-N-(2-OXO-2,5-DIHYDROPYRIDIN-4-YL)BENZAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / phosphotransfer catalyst / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of NK T cell proliferation / Interleukin-12 signaling ...type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of NK T cell proliferation / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / extrinsic component of cytoplasmic side of plasma membrane / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-10 signaling / positive regulation of interleukin-17 production / positive regulation of natural killer cell proliferation / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / non-membrane spanning protein tyrosine kinase activity / positive regulation of receptor signaling pathway via JAK-STAT / non-specific protein-tyrosine kinase / Inactivation of CSF3 (G-CSF) signaling / cellular response to virus / positive regulation of protein localization to nucleus / Evasion by RSV of host interferon responses / cytoplasmic side of plasma membrane / positive regulation of type II interferon production / cytokine-mediated signaling pathway / Interferon alpha/beta signaling / Signaling by ALK fusions and activated point mutants / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cytoskeleton / cell differentiation / protein phosphorylation / receptor complex / cell population proliferation / intracellular signal transduction / immune response / 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 / SH2 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 / SH2 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-0X2 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsEigenbrot, C. / Ultsch, M.
CitationJournal: Eur.J.Med.Chem. / Year: 2013
Title: Lead identification of novel and selective TYK2 inhibitors.
Authors: Liang, J. / Tsui, V. / Van Abbema, A. / Bao, L. / Barrett, K. / Beresini, M. / Berezhkovskiy, L. / Blair, W.S. / Chang, C. / Driscoll, J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / ...Authors: Liang, J. / Tsui, V. / Van Abbema, A. / Bao, L. / Barrett, K. / Beresini, M. / Berezhkovskiy, L. / Blair, W.S. / Chang, C. / Driscoll, J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Halladay, J. / Johnson, A. / Kohli, P.B. / Lai, Y. / Liimatta, M. / Mantik, P. / Menghrajani, K. / Murray, J. / Sambrone, A. / Xiao, Y. / Shia, S. / Shin, Y. / Smith, J. / Sohn, S. / Stanley, M. / Ultsch, M. / Zhang, B. / Wu, L.C. / Magnuson, S.
History
DepositionAug 3, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Database references
Revision 1.2Sep 13, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,6947
Polymers35,0021
Non-polymers6916
Water1,40578
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.361, 49.361, 420.686
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 35002.059 Da / Num. of mol.: 1 / Fragment: JH1 domain, UNP residues 884-1176 / Mutation: D1023N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 84 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-0X2 / 2,6-dichloro-N-(2-oxo-2,5-dihydropyridin-4-yl)benzamide


Mass: 283.110 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H8Cl2N2O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 2.11 Å3/Da / Density % sol: 41.8 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 2 M ammonium sulfate, pH 5, VAPOR DIFFUSION, SITTING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Nov 13, 2008
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 171418 / Num. obs: 171418 / % possible obs: 92.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 12 % / Biso Wilson estimate: 41.01 Å2 / Rsym value: 0.072 / Net I/σ(I): 39

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
BUSTER2.11.2refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NZ0

3nz0


Resolution: 2.3→42.53 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.8673 / SU R Cruickshank DPI: 0.423 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2868 713 5.16 %RANDOM
Rwork0.2341 ---
obs0.2367 13821 93.16 %-
all-13821 --
Displacement parametersBiso mean: 50.75 Å2
Baniso -1Baniso -2Baniso -3
1--4.1471 Å20 Å20 Å2
2---4.1471 Å20 Å2
3---8.2943 Å2
Refine analyzeLuzzati coordinate error obs: 0.454 Å
Refinement stepCycle: LAST / Resolution: 2.3→42.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2236 0 42 78 2356
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082413HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.023273HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d838SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes51HARMONIC2
X-RAY DIFFRACTIONt_gen_planes351HARMONIC5
X-RAY DIFFRACTIONt_it2413HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.53
X-RAY DIFFRACTIONt_other_torsion19.83
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion287SEMIHARMONIC5
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_contact2832SEMIHARMONIC4
LS refinement shellResolution: 2.3→2.48 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2757 98 4.84 %
Rwork0.2526 1925 -
all0.2539 2023 -
obs--93.16 %
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)
15.3208-2.07630.12070.9971.02622.4651-0.2431-0.093-0.16660.26810.11240.10920.0336-0.6090.13070.10710.03830.0980.4138-0.0323-0.14789.3855-19.6230.8899
21.773-0.36861.33730.4171-0.15193.4817-0.3188-0.3110.10690.03940.1381-0.0577-0.3357-0.37950.1807-0.10190.0791-0.02430.1577-0.0775-0.080625.0262-16.260111.127
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|890 - A|979 }A890 - 979
2X-RAY DIFFRACTION2{ A|980 - A|1178 A|1206 - A|1206 }A980 - 1178
3X-RAY DIFFRACTION2{ A|980 - A|1178 A|1206 - A|1206 }A1206

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