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- PDB-4py1: Crystal structure of Tyk2 in complex with compound 15, 6-((2,5-di... -

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Basic information

Entry
Database: PDB / ID: 4py1
TitleCrystal structure of Tyk2 in complex with compound 15, 6-((2,5-dimethoxyphenyl)thio)-3-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / kinase
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 / 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 / non-specific protein-tyrosine kinase / cellular response to virus / positive regulation of protein localization to nucleus / cytoplasmic side of plasma membrane / Interferon alpha/beta signaling / positive regulation of type II interferon production / Signaling by ALK fusions and activated point mutants / cytokine-mediated signaling pathway / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / cell population proliferation / receptor complex / intracellular signal transduction / protein phosphorylation / immune response / 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 / 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-2YK / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsHan, S. / Knafels, J.D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffold.
Authors: Galatsis, P. / Henderson, J.L. / Kormos, B.L. / Han, S. / Kurumbail, R.G. / Wager, T.T. / Verhoest, P.R. / Noell, G.S. / Chen, Y. / Needle, E. / Berger, Z. / Steyn, S.J. / Houle, C. / Hirst, W.D.
History
DepositionMar 25, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 3, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 17, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Mar 6, 2024Group: 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 / software / struct_conn / 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 / _software.name / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)36,9192
Polymers36,5511
Non-polymers3681
Water2,126118
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.470, 73.510, 103.630
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 36550.570 Da / Num. of mol.: 1 / Mutation: C936A, Q969A, E971A, K972A, C1142A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: Escherichia coli (E. coli)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-2YK / 6-[(2,5-dimethoxyphenyl)sulfanyl]-3-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazine


Mass: 368.413 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16N6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 1.9 Å3/Da / Density % sol: 35.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.1 M Bis-tris pH 5.5, 250 mM NaCl, 10 mM TCEP, 33-40% PEG-3350, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 173 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 1, 2011
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.156→36.8 Å / Num. obs: 15340 / % possible obs: 97.1 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Biso Wilson estimate: 39.15 Å2 / Rmerge(I) obs: 0.07
Reflection shellResolution: 2.156→2.163 Å / % possible all: 91.7

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Processing

Software
NameClassification
autoPROCdata collection
BUSTERrefinement
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.16→36.75 Å / Cor.coef. Fo:Fc: 0.9475 / Cor.coef. Fo:Fc free: 0.9192 / SU R Cruickshank DPI: 0.27 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2364 1017 6.68 %RANDOM
Rwork0.1806 ---
obs0.1844 15222 97.78 %-
all-15340 --
Displacement parametersBiso mean: 46.73 Å2
Baniso -1Baniso -2Baniso -3
1-0.2906 Å20 Å20 Å2
2--5.8227 Å20 Å2
3----6.1133 Å2
Refine analyzeLuzzati coordinate error obs: 0.301 Å
Refinement stepCycle: LAST / Resolution: 2.16→36.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2349 0 26 118 2493
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012442HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.093310HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d835SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes55HARMONIC2
X-RAY DIFFRACTIONt_gen_planes383HARMONIC5
X-RAY DIFFRACTIONt_it2442HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.14
X-RAY DIFFRACTIONt_other_torsion19.88
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion293SEMIHARMONIC5
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_contact2855SEMIHARMONIC4
LS refinement shellResolution: 2.16→2.31 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2504 178 6.68 %
Rwork0.2029 2488 -
all0.2062 2666 -
obs--97.78 %
Refinement TLS params.Method: refined / Origin x: 11.2757 Å / Origin y: 1.4047 Å / Origin z: 15.6893 Å
111213212223313233
T-0.1272 Å20.0284 Å20.0226 Å2--0.0817 Å20.0136 Å2---0.0895 Å2
L0.7201 °20.5023 °20.1577 °2-4.275 °2-0.3446 °2--1.5252 °2
S0.0368 Å °0.0821 Å °0.0617 Å °-0.3775 Å °-0.1145 Å °-0.325 Å °0.1828 Å °0.1159 Å °0.0777 Å °
Refinement TLS groupSelection details: { A|* }

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