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- PDB-4e20: Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor -

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Basic information

Entry
Database: PDB / ID: 4.0E+20
TitleStructure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase catalytic domain / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Interleukin-10 signaling / Interleukin-4 and Interleukin-13 signaling / Regulation of IFNA/IFNB signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-20 family signaling / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-12 signaling / Interleukin-27 signaling / Signaling by CSF3 (G-CSF) ...Interleukin-10 signaling / Interleukin-4 and Interleukin-13 signaling / Regulation of IFNA/IFNB signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-20 family signaling / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-12 signaling / Interleukin-27 signaling / Signaling by CSF3 (G-CSF) / Interleukin-23 signaling / Interleukin-6 signaling / Interleukin-35 Signalling / Interferon alpha/beta signaling / Inactivation of CSF3 (G-CSF) signaling / interleukin-12 receptor complex / interleukin-23 receptor complex / 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 / growth hormone receptor binding / positive regulation of natural killer cell proliferation / type I interferon-mediated signaling pathway / positive regulation of interleukin-17 production / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / 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 / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / positive regulation of type II interferon production / protein tyrosine kinase activity / cell population proliferation / cell differentiation / cytoskeleton / intracellular signal transduction / immune response / phosphorylation / 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 / 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-0MY / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsArgiriadi, M.A. / Talanian, R.V. / Borhani, D.W.
CitationJournal: Bmc Struct.Biol. / Year: 2012
Title: Enabling structure-based drug design of Tyk2 through co-crystallization with a stabilizing aminoindazole inhibitor.
Authors: Argiriadi, M.A. / Goedken, E.R. / Banach, D. / Borhani, D.W. / Burchat, A. / Dixon, R.W. / Marcotte, D. / Overmeyer, G. / Pivorunas, V. / Sadhukhan, R. / Sousa, S. / Moore, N.S. / Tomlinson, ...Authors: Argiriadi, M.A. / Goedken, E.R. / Banach, D. / Borhani, D.W. / Burchat, A. / Dixon, R.W. / Marcotte, D. / Overmeyer, G. / Pivorunas, V. / Sadhukhan, R. / Sousa, S. / Moore, N.S. / Tomlinson, M. / Voss, J. / Wang, L. / Wishart, N. / Woller, K. / Talanian, R.V.
History
DepositionMar 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,0082
Polymers33,6091
Non-polymers3991
Water1,71195
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.280, 67.280, 154.912
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 33609.453 Da / Num. of mol.: 1 / Fragment: Tyk-2 catalytic domain (UNP Residues 881-1170) / Mutation: D1016A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Tyk2 / Plasmid: pDEST20 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9R117, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0MY / N-[4-(3-amino-1H-indazol-5-yl)phenyl]-3-chlorobenzenesulfonamide


Mass: 398.866 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15ClN4O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 95 / 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: 3.01 Å3/Da / Density % sol: 59.16 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 4.3-4.7 M ammonium formate, 100 mM Tris pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Oct 29, 2006
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. all: 13121 / Num. obs: 13121 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 63.59 Å2
Reflection shellResolution: 2.6→2.64 Å / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
BUSTER2.9.7refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→38.65 Å / Cor.coef. Fo:Fc: 0.9352 / Cor.coef. Fo:Fc free: 0.9261 / SU R Cruickshank DPI: 0.435 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2325 640 4.9 %RANDOM
Rwork0.1986 ---
obs0.2003 13072 99.89 %-
all-13072 --
Displacement parametersBiso mean: 50.46 Å2
Baniso -1Baniso -2Baniso -3
1-0.2757 Å20 Å20 Å2
2--0.2757 Å20 Å2
3----0.5514 Å2
Refine analyzeLuzzati coordinate error obs: 0.318 Å
Refinement stepCycle: LAST / Resolution: 2.6→38.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2299 0 27 95 2421
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012387HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.153233HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d822SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes56HARMONIC2
X-RAY DIFFRACTIONt_gen_planes343HARMONIC5
X-RAY DIFFRACTIONt_it2387HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion21.06
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion286SEMIHARMONIC5
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_contact2683SEMIHARMONIC4
LS refinement shellResolution: 2.6→2.81 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2896 132 4.97 %
Rwork0.2336 2525 -
all0.2363 2657 -
obs--99.89 %

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