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- PDB-6vnv: Crystal structure of TYK2 kinase with compound 14 -

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Basic information

Entry
Database: PDB / ID: 6vnv
TitleCrystal structure of TYK2 kinase with compound 14
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/INHIBITOR / kinase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
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 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / 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 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / 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 / extrinsic component of plasma membrane / Other interleukin signaling / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / Interleukin-6 signaling / MAPK3 (ERK1) activation / extrinsic component of cytoplasmic side of plasma membrane / 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 / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / positive regulation of receptor signaling pathway via JAK-STAT / Inactivation of CSF3 (G-CSF) signaling / cellular response to virus / Evasion by RSV of host interferon responses / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / cytoplasmic side of plasma membrane / positive regulation of type II interferon production / Interferon alpha/beta signaling / 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 / 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 ...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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-R4Y / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsVajdos, F.F.
CitationJournal: Bioorg.Med.Chem. / Year: 2020
Title: Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1.
Authors: Fensome, A. / Ambler, C.M. / Arnold, E. / Banker, M.E. / Clark, J.D. / Dowty, M.E. / Efremov, I.V. / Flick, A. / Gerstenberger, B.S. / Gifford, R.S. / Gopalsamy, A. / Hegen, M. / Jussif, J. ...Authors: Fensome, A. / Ambler, C.M. / Arnold, E. / Banker, M.E. / Clark, J.D. / Dowty, M.E. / Efremov, I.V. / Flick, A. / Gerstenberger, B.S. / Gifford, R.S. / Gopalsamy, A. / Hegen, M. / Jussif, J. / Limburg, D.C. / Lin, T.H. / Pierce, B.S. / Sharma, R. / Trujillo, J.I. / Vajdos, F.F. / Vincent, F. / Wan, Z.K. / Xing, L. / Yang, X. / Yang, X.
History
DepositionJan 29, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 29, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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)36,9632
Polymers36,5511
Non-polymers4121
Water2,504139
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)35.873, 72.714, 98.465
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 / Fragment: kinase domain / Mutation: C936A, C1142A, Q969A, E971A, K972A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-R4Y / (1S,2S)-2-cyano-N-[(1S,5R)-3-(5-fluoro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]cyclopropane-1-carboxamide


Mass: 412.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21FN8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 139 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.76 Å3/Da / Density % sol: 29.98 % / Mosaicity: 0 °
Crystal growTemperature: 298 K / Method: evaporation / pH: 8
Details: 0.1 M bis-tris pH 5.5, 0.25 M NaCl, 10 mM TCEP, 27-33% PEG-3350

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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: Nov 15, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→98.465 Å / Num. obs: 14330 / % possible obs: 98.1 % / Redundancy: 4.9 % / Biso Wilson estimate: 33.86 Å2 / Rpim(I) all: 0.047 / Rrim(I) all: 0.112 / Rsym value: 0.091 / Net I/av σ(I): 6.6 / Net I/σ(I): 11.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
2.15-2.272.50.2752.818420.250.4180.27588.9
2.27-2.413.20.2572.919370.1860.3490.25798.4
2.41-2.574.10.251318510.1530.3170.25199.9
2.57-2.785.80.2233.317610.1080.2640.223100
2.78-3.046.50.1764.115940.0810.2060.17699.9
3.04-3.46.10.1116.214740.0540.1330.111100
3.4-3.936.30.0768.713120.0370.0920.076100
3.93-4.815.80.0649.811180.0320.0790.064100
4.81-6.815.90.06210.29000.030.0740.06299.9
6.81-98.4655.30.04612.55410.0220.0540.04699.6

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER2.11.2refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LXP

3lxp


Resolution: 2.15→58.49 Å / Cor.coef. Fo:Fc: 0.9215 / Cor.coef. Fo:Fc free: 0.899 / SU R Cruickshank DPI: 0.293 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.323 / SU Rfree Blow DPI: 0.216 / SU Rfree Cruickshank DPI: 0.211
RfactorNum. reflection% reflectionSelection details
Rfree0.2379 729 5.1 %RANDOM
Rwork0.1858 ---
obs0.1885 14285 97.6 %-
Displacement parametersBiso max: 135.03 Å2 / Biso mean: 39.2 Å2 / Biso min: 15.42 Å2
Baniso -1Baniso -2Baniso -3
1-8.7082 Å20 Å20 Å2
2--4.6273 Å20 Å2
3----13.3355 Å2
Refine analyzeLuzzati coordinate error obs: 0.246 Å
Refinement stepCycle: final / Resolution: 2.15→58.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2246 0 30 139 2415
Biso mean--26.99 41.85 -
Num. residues----275
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d814SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes354HARMONIC5
X-RAY DIFFRACTIONt_it2359HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion285SEMIHARMONIC5
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_contact2918SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2359HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3217HARMONIC21.17
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion20.98
LS refinement shellResolution: 2.15→2.32 Å / Rfactor Rfree error: 0 / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.285 130 4.96 %
Rwork0.197 2493 -
all0.2012 2623 -
obs--97.6 %

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