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- PDB-4wov: CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN)... -

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Basic information

Entry
Database: PDB / ID: 4wov
TitleCRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH BMS-066 AKA 2-METHOXY-N-({6-[3-METHYL-7-(METHYLAMINO)-3,5,8,10-TETRAAZATRICYCLO[7.3.0.0, 6]DODECA-1(9),2(6),4,7,11-PENTAEN-11-YL]PYRIDIN-2-YL}METHY L)ACETAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/INHIBITOR / KINASE / TYK2 / PSEUDOKINASE / 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 / 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-3SM / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsMuckelbauer, J.K.
CitationJournal: J.Biol.Chem. / Year: 2015
Title: Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain.
Authors: Tokarski, J.S. / Zupa-Fernandez, A. / Tredup, J.A. / Pike, K. / Chang, C. / Xie, D. / Cheng, L. / Pedicord, D. / Muckelbauer, J. / Johnson, S.R. / Wu, S. / Edavettal, S.C. / Hong, Y. / ...Authors: Tokarski, J.S. / Zupa-Fernandez, A. / Tredup, J.A. / Pike, K. / Chang, C. / Xie, D. / Cheng, L. / Pedicord, D. / Muckelbauer, J. / Johnson, S.R. / Wu, S. / Edavettal, S.C. / Hong, Y. / Witmer, M.R. / Elkin, L.L. / Blat, Y. / Pitts, W.J. / Weinstein, D.S. / Burke, J.R.
History
DepositionOct 16, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 15, 2015Group: Database references
Revision 1.2May 13, 2015Group: Database references
Revision 1.3Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _software.name
Revision 1.4Dec 27, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)72,2379
Polymers70,9982
Non-polymers1,2397
Water4,630257
1
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0714
Polymers35,4991
Non-polymers5723
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1675
Polymers35,4991
Non-polymers6684
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2130 Å2
ΔGint-95 kcal/mol
Surface area21980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.544, 63.579, 68.016
Angle α, β, γ (deg.)74.32, 75.48, 88.20
Int Tables number1
Space group name H-MP1

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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 (UNP residues 575-869)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: unidentified baculovirus
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-3SM / 2-methoxy-N-({6-[1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]pyridin-2-yl}methyl)acetamide


Mass: 379.416 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H21N7O2
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 1.97 Å3/Da / Density % sol: 39.55 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 30% PEG5000 (methyl ether), 200 mM ammonium sulfate and 100 mM sodium cacodylate buffer, pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.979 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Sep 12, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 57908 / % possible obs: 97.7 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 28.85 Å2 / Rmerge(I) obs: 0.067 / Net I/σ(I): 16.6
Reflection shellHighest resolution: 3.88 Å / Redundancy: 4 % / Mean I/σ(I) obs: 24.8 / % possible all: 99.4

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.11.5refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→36 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.9388 / SU R Cruickshank DPI: 0.112 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.11 / SU Rfree Blow DPI: 0.103 / SU Rfree Cruickshank DPI: 0.105
RfactorNum. reflection% reflectionSelection details
Rfree0.2144 2919 5.04 %RANDOM
Rwork0.1918 ---
obs0.1929 57869 96.32 %-
Displacement parametersBiso mean: 31.59 Å2
Baniso -1Baniso -2Baniso -3
1-3.9025 Å2-5.5919 Å2-3.0993 Å2
2---5.5394 Å2-1.299 Å2
3---1.6369 Å2
Refine analyzeLuzzati coordinate error obs: 0.217 Å
Refinement stepCycle: 1 / Resolution: 1.8→36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3861 0 81 257 4199
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014081HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.975605HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1309SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes62HARMONIC2
X-RAY DIFFRACTIONt_gen_planes680HARMONIC5
X-RAY DIFFRACTIONt_it4081HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.31
X-RAY DIFFRACTIONt_other_torsion14.45
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion526SEMIHARMONIC5
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_contact4756SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2462 197 5.74 %
Rwork0.235 3236 -
all0.2356 3433 -
obs--96.32 %

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