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- PDB-8tb6: TYK2 JH2 bound to Compound14 -

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Basic information

Entry
Database: PDB / ID: 8tb6
TitleTYK2 JH2 bound to Compound14
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsSIGNALING PROTEIN / TYK2 / pseudokinase / azaindole
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / 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 / Interleukin-12 signaling / Interleukin-35 Signalling ...type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / 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 / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / growth hormone receptor binding / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / Interleukin-10 signaling / MAPK1 (ERK2) activation / positive regulation of natural killer cell proliferation / 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 / Signaling by CSF3 (G-CSF) / 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 / Inactivation of CSF3 (G-CSF) signaling / 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 / 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 / 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 / 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-ZOI / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 Å
AuthorsArgiriadi, M.A. / Van Epps, S.A. / Breinlinger, E.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Targeting the Tyrosine Kinase 2 (TYK2) Pseudokinase Domain: Discovery of the Selective TYK2 Inhibitor ABBV-712.
Authors: Breinlinger, E. / Van Epps, S. / Friedman, M. / Argiriadi, M. / Chien, E. / Chhor, G. / Cowart, M. / Dunstan, T. / Graff, C. / Hardee, D. / Herold, J.M. / Little, A. / McCarthy, R. / ...Authors: Breinlinger, E. / Van Epps, S. / Friedman, M. / Argiriadi, M. / Chien, E. / Chhor, G. / Cowart, M. / Dunstan, T. / Graff, C. / Hardee, D. / Herold, J.M. / Little, A. / McCarthy, R. / Parmentier, J. / Perham, M. / Qiu, W. / Schrimpf, M. / Vargo, T. / Webster, M.P. / Wu, F. / Bennett, D. / Edmunds, J.
History
DepositionJun 28, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 8, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)73,7214
Polymers72,9872
Non-polymers7352
Water4,360242
1
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8612
Polymers36,4931
Non-polymers3671
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)36,8612
Polymers36,4931
Non-polymers3671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.470, 47.715, 119.313
Angle α, β, γ (deg.)90.000, 91.080, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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


Mass: 36493.301 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-ZOI / N-[(3M)-3-{6-[(3R)-3-methoxyoxolan-3-yl]pyridin-2-yl}-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl]urea


Mass: 367.402 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H21N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 242 / 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: 2.05 Å3/Da / Density % sol: 39.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 30% w/v PEG4,000, 200mM Sodium Acetate, 100mM Tris-HCl pH8.5

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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 EIGER X 9M / Detector: PIXEL / Date: Apr 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.955→59.7 Å / Num. obs: 42368 / % possible obs: 98.3 % / Redundancy: 3.3 % / Biso Wilson estimate: 28.09 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.081 / Net I/σ(I): 12.5
Reflection shellResolution: 1.955→1.989 Å / Rmerge(I) obs: 0.689 / Num. unique obs: 2092 / CC1/2: 0.634

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Processing

Software
NameVersionClassification
BUSTERrefinement
PHENIX1.19.2_4158refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.96→19.76 Å / SU ML: 0.2513 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.7372
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2358 2067 4.92 %
Rwork0.1925 39950 -
obs0.1947 42017 98.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.22 Å2
Refinement stepCycle: LAST / Resolution: 1.96→19.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3975 0 54 242 4271
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00664142
X-RAY DIFFRACTIONf_angle_d0.94655644
X-RAY DIFFRACTIONf_chiral_restr0.0527643
X-RAY DIFFRACTIONf_plane_restr0.0073732
X-RAY DIFFRACTIONf_dihedral_angle_d4.9976565
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.96-2.010.33421340.2682605X-RAY DIFFRACTION97.65
2.01-2.060.30841230.25482658X-RAY DIFFRACTION98.2
2.06-2.110.29961200.23832604X-RAY DIFFRACTION96.91
2.11-2.170.29091460.22852681X-RAY DIFFRACTION98.3
2.17-2.240.23911270.21232602X-RAY DIFFRACTION98.2
2.24-2.320.31171200.20892664X-RAY DIFFRACTION98.48
2.32-2.420.25681620.20382680X-RAY DIFFRACTION98.92
2.42-2.530.24081220.20212698X-RAY DIFFRACTION98.98
2.53-2.660.28361470.19972674X-RAY DIFFRACTION99.33
2.66-2.820.21891390.19852667X-RAY DIFFRACTION98.98
2.83-3.040.24411430.19412672X-RAY DIFFRACTION98.7
3.04-3.350.251320.18032679X-RAY DIFFRACTION98.25
3.35-3.830.22741660.17332621X-RAY DIFFRACTION97.31
3.83-4.810.18341320.15782698X-RAY DIFFRACTION97.62
4.81-19.760.20021540.19262747X-RAY DIFFRACTION98.14

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