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

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Basic information

Entry
Database: PDB / ID: 6nzq
TitleCRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound_29 AKA 6-[(5-FLUORO-4-METH YLPYRIDIN-2-YL)AMINO]-4-({2-METHOXY-3-[(PYRIDIN-2-YLMETHYL )CARBAMOYL]PHENYL}AMINO)-N-METHYLPYRIDINE-3-CARBOXAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / JTK1 / PSEUDOKINASE
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 / 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-LB4 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsKhan, J.A.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.
Authors: Wrobleski, S.T. / Moslin, R. / Lin, S. / Zhang, Y. / Spergel, S. / Kempson, J. / Tokarski, J.S. / Strnad, J. / Zupa-Fernandez, A. / Cheng, L. / Shuster, D. / Gillooly, K. / Yang, X. / ...Authors: Wrobleski, S.T. / Moslin, R. / Lin, S. / Zhang, Y. / Spergel, S. / Kempson, J. / Tokarski, J.S. / Strnad, J. / Zupa-Fernandez, A. / Cheng, L. / Shuster, D. / Gillooly, K. / Yang, X. / Heimrich, E. / McIntyre, K.W. / Chaudhry, C. / Khan, J. / Ruzanov, M. / Tredup, J. / Mulligan, D. / Xie, D. / Sun, H. / Huang, C. / D'Arienzo, C. / Aranibar, N. / Chiney, M. / Chimalakonda, A. / Pitts, W.J. / Lombardo, L. / Carter, P.H. / Burke, J.R. / Weinstein, D.S.
History
DepositionFeb 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 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

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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)72,0294
Polymers70,9982
Non-polymers1,0312
Water1,51384
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint1 kcal/mol
Surface area22540 Å2
2
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0152
Polymers35,4991
Non-polymers5161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0152
Polymers35,4991
Non-polymers5161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.010, 67.450, 75.120
Angle α, β, γ (deg.)90.00, 112.73, 90.00
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: Pseudo kinase domain, residues 575-869
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-LB4 / 6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-[(2-methoxy-3-{[(pyridin-2-yl)methyl]carbamoyl}phenyl)amino]-N-methylpyridine-3-carboxamide


Mass: 515.539 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H26FN7O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 84 / 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: 2.34 Å3/Da / Density % sol: 47.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 200 mM ammonium sulfate, and 100 mM Sodium Cacodylate, pH 6.5, 30%(W/V) PEG 5000 (Methyl Ether)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 7, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.11→69.29 Å / Num. obs: 19966 / % possible obs: 89.3 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 47.48 Å2 / Rmerge(I) obs: 0.103 / Rsym value: 0.02 / Net I/σ(I): 7.4
Reflection shellResolution: 2.12→2.42 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.06 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 19960 / Rsym value: 0.062 / % possible all: 56

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WOV

4wov


Resolution: 2.11→69.29 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.901 / SU R Cruickshank DPI: 0.576 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.518 / SU Rfree Blow DPI: 0.273 / SU Rfree Cruickshank DPI: 0.28
RfactorNum. reflection% reflectionSelection details
Rfree0.237 1037 5.19 %RANDOM
Rwork0.197 ---
obs0.199 19966 52.7 %-
Displacement parametersBiso mean: 47.13 Å2
Baniso -1Baniso -2Baniso -3
1-0.772 Å20 Å20.1009 Å2
2--0.4855 Å20 Å2
3----1.2574 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 2.11→69.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3952 0 76 84 4112
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014191HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.135740HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1394SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes786HARMONIC5
X-RAY DIFFRACTIONt_it4191HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3
X-RAY DIFFRACTIONt_other_torsion20.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion528SEMIHARMONIC5
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_contact4761SEMIHARMONIC4
LS refinement shellResolution: 2.11→2.31 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2971 -5.75 %
Rwork0.2282 377 -
all0.2317 400 -
obs--4.46 %

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