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- PDB-5tkd: CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN)... -

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Basic information

Entry
Database: PDB / ID: 5tkd
TitleCRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH 6-[(3,5-DIMETHYLPHE NYL)AMINO]-8- (METHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBO XAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / KINASE / TYK2 / PSEUDOKINASE
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
Chem-7GL / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsMuckelbauer, J.K.
CitationJournal: Medchemcomm / Year: 2017
Title: Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling.
Authors: Moslin, R. / Gardner, D. / Santella, J. / Zhang, Y. / Duncia, J.V. / Liu, C. / Lin, J. / Tokarski, J.S. / Strnad, J. / Pedicord, D. / Chen, J. / Blat, Y. / Zupa-Fernandez, A. / Cheng, L. / ...Authors: Moslin, R. / Gardner, D. / Santella, J. / Zhang, Y. / Duncia, J.V. / Liu, C. / Lin, J. / Tokarski, J.S. / Strnad, J. / Pedicord, D. / Chen, J. / Blat, Y. / Zupa-Fernandez, A. / Cheng, L. / Sun, H. / Chaudhry, C. / Huang, C. / D'Arienzo, C. / Sack, J.S. / Muckelbauer, J.K. / Chang, C. / Tredup, J. / Xie, D. / Aranibar, N. / Burke, J.R. / Carter, P.H. / Weinstein, D.S.
History
DepositionOct 6, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / 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)67,5397
Polymers66,6302
Non-polymers9095
Water3,405189
1
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7213
Polymers33,3151
Non-polymers4062
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)33,8174
Polymers33,3151
Non-polymers5023
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
B: Non-receptor tyrosine-protein kinase TYK2
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)67,5397
Polymers66,6302
Non-polymers9095
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
Buried area1650 Å2
ΔGint-52 kcal/mol
Surface area21290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.599, 65.702, 74.702
Angle α, β, γ (deg.)90.000, 112.420, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 33314.832 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 / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-7GL / 6-[(3,5-dimethylphenyl)amino]-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide


Mass: 310.354 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18N6O
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 189 / 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: 2.37 Å3/Da / Density % sol: 48.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.5

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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: Jun 9, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.92→47.6 Å / Num. obs: 47129 / % possible obs: 98.9 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 29.23 Å2 / Rsym value: 0.077 / Net I/σ(I): 9.5
Reflection shellResolution: 1.92→2.02 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 2.4 / % possible all: 99.1

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.7refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WOV

4wov


Resolution: 1.92→28.11 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.133 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.131 / SU Rfree Blow DPI: 0.119 / SU Rfree Cruickshank DPI: 0.121
RfactorNum. reflection% reflectionSelection details
Rfree0.215 2371 5.04 %RANDOM
Rwork0.192 ---
obs0.193 47061 98.6 %-
Displacement parametersBiso max: 91.63 Å2 / Biso mean: 28.94 Å2 / Biso min: 13.86 Å2
Baniso -1Baniso -2Baniso -3
1-1.6627 Å20 Å2-0.7813 Å2
2--0.2623 Å20 Å2
3----1.925 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: final / Resolution: 1.92→28.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3753 0 61 189 4003
Biso mean--26.45 35.69 -
Num. residues----495
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1273SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes64HARMONIC2
X-RAY DIFFRACTIONt_gen_planes641HARMONIC5
X-RAY DIFFRACTIONt_it3938HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion506SEMIHARMONIC5
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_contact4532SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3938HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5381HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.41
X-RAY DIFFRACTIONt_other_torsion15.18
LS refinement shellResolution: 1.92→1.97 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.233 189 5.47 %
Rwork0.197 3265 -
all-3454 -
obs--98.75 %

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