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

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Basic information

Entry
Database: PDB / ID: 6nsl
TitleCRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound-6c AKA 6-((1-(4-CYANOPHENY L)-2-OXO-1,2-DIHYDRO-3-PYRIDINYL)AMINO)-N-CYCLOPROPYL-8-(M ETHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBOXAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / KINASE
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-KZJ / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.15 Å
AuthorsMuckelbauer, J.M. / Khan, J.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors.
Authors: Liu, C. / Lin, J. / Moslin, R. / Tokarski, J.S. / Muckelbauer, J. / Chang, C. / Tredup, J. / Xie, D. / Park, H. / Li, P. / Wu, D.R. / Strnad, J. / Zupa-Fernandez, A. / Cheng, L. / Chaudhry, ...Authors: Liu, C. / Lin, J. / Moslin, R. / Tokarski, J.S. / Muckelbauer, J. / Chang, C. / Tredup, J. / Xie, D. / Park, H. / Li, P. / Wu, D.R. / Strnad, J. / Zupa-Fernandez, A. / Cheng, L. / Chaudhry, C. / Chen, J. / Chen, C. / Sun, H. / Elzinga, P. / D'arienzo, C. / Gillooly, K. / Taylor, T.L. / McIntyre, K.W. / Salter-Cid, L. / Lombardo, L.J. / Carter, P.H. / Aranibar, N. / Burke, J.R. / Weinstein, D.S.
History
DepositionJan 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 15, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _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
Revision 1.2Mar 13, 2024Group: 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)72,1677
Polymers70,9982
Non-polymers1,1695
Water1,76598
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A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0363
Polymers35,4991
Non-polymers5372
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1324
Polymers35,4991
Non-polymers6333
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.015, 65.654, 74.680
Angle α, β, γ (deg.)90.000, 112.700, 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: 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-KZJ / 6-{[1-(4-cyanophenyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}-N-cyclopropyl-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide


Mass: 440.457 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H20N8O2 / Feature type: SUBJECT OF INVESTIGATION
#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.: 98 / 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: 1.92 Å3/Da / Density % sol: 36.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 200 mM ammonium sulfate, and 100 mM sodium cacodylate buffer, pH 6.5, 30%(W/V) PEG 5000 (Methyl Ether)
PH range: 6.5

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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: Mar 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→47.53 Å / Num. obs: 33875 / % possible obs: 99.3 % / Redundancy: 3.3 % / Biso Wilson estimate: 43.25 Å2 / Rsym value: 0.047 / Net I/σ(I): 15.6
Reflection shellResolution: 6.8→47.53 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 48.9 / Rsym value: 0.015 / % possible all: 97

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.15→28.94 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.929 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.201 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.194 / SU Rfree Blow DPI: 0.151 / SU Rfree Cruickshank DPI: 0.155
RfactorNum. reflection% reflectionSelection details
Rfree0.213 1716 5.07 %RANDOM
Rwork0.202 ---
obs0.203 33839 99 %-
Displacement parametersBiso max: 107.78 Å2 / Biso mean: 41.78 Å2 / Biso min: 23.43 Å2
Baniso -1Baniso -2Baniso -3
1--1.5435 Å20 Å2-0.4727 Å2
2---8.4124 Å20 Å2
3---9.9559 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 2.15→28.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3708 0 121 98 3927
Biso mean--37.43 41.44 -
Num. residues----499
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1238SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes59HARMONIC2
X-RAY DIFFRACTIONt_gen_planes667HARMONIC5
X-RAY DIFFRACTIONt_it3924HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion509SEMIHARMONIC5
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_contact4428SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3924HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5392HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion15.19
LS refinement shellResolution: 2.15→2.22 Å / Rfactor Rfree error: 0 / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.261 143 4.95 %
Rwork0.212 2745 -
all0.215 2888 -
obs--97.76 %

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