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

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Basic information

Entry
Database: PDB / ID: 6nzr
TitleCRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound_12 AKA 4-[(2-methanesulfonylphenyl)amino]-N-(H3)methyl-6-[(pyridin-2- yl)amino]pyridazine-3-carboxamide
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / JTK1 / PSEUDOKINASE
Function / homology
Function and homology information


hydrogenase (acceptor) / hydrogenase (acceptor) activity / ferredoxin hydrogenase activity / nickel cation binding / plasma membrane
Similarity search - Function
: / Nickel-dependent hydrogenases large subunit signature 2. / Nickel-dependent hydrogenases large subunit signature 1. / Nickel-dependent hydrogenase, large subunit, nickel binding site / Nickel-dependent hydrogenase, large subunit / Nickel-dependent hydrogenase / [NiFe]-hydrogenase, large subunit / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...: / Nickel-dependent hydrogenases large subunit signature 2. / Nickel-dependent hydrogenases large subunit signature 1. / Nickel-dependent hydrogenase, large subunit, nickel binding site / Nickel-dependent hydrogenase, large subunit / Nickel-dependent hydrogenase / [NiFe]-hydrogenase, large subunit / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-LAJ / Hydrogenase-2 large chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.56 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

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)71,9636
Polymers70,9742
Non-polymers9894
Water1,60389
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1440 Å2
ΔGint-34 kcal/mol
Surface area22750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.430, 66.480, 75.390
Angle α, β, γ (deg.)90.00, 113.16, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 35487.102 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-LAJ / N-methyl-4-{[2-(methylsulfonyl)phenyl]amino}-6-[(pyridin-2-yl)amino]pyridazine-3-carboxamide


Mass: 398.439 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H18N6O3S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / 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: 2.29 Å3/Da / Density % sol: 46.18 %
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 29, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→60.7 Å / Num. obs: 25776 / % possible obs: 86.3 % / Observed criterion σ(I): 0 / Redundancy: 3.3 % / Biso Wilson estimate: 61.86 Å2 / Rmerge(I) obs: 0.113 / Rsym value: 0.07 / Net I/σ(I): 6.7
Reflection shellResolution: 2.05→2.3 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.07 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 25776 / Rsym value: 0.074 / % possible all: 54.3

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Processing

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

4wov


Resolution: 2.56→25.71 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.901 / SU R Cruickshank DPI: 0.592 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.546 / SU Rfree Blow DPI: 0.268 / SU Rfree Cruickshank DPI: 0.274
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1001 5.06 %RANDOM
Rwork0.188 ---
obs0.19 19770 94.7 %-
Displacement parametersBiso mean: 51.93 Å2
Baniso -1Baniso -2Baniso -3
1-9.4279 Å20 Å2-1.555 Å2
2---13.1475 Å20 Å2
3---3.7197 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 2.56→25.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4008 0 66 89 4163
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014239HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.095790HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1424SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes773HARMONIC5
X-RAY DIFFRACTIONt_it4239HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion18.37
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion531SEMIHARMONIC5
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_contact4674SEMIHARMONIC4
LS refinement shellResolution: 2.56→2.57 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2032 -4.55 %
Rwork0.232 378 -
all0.2305 396 -
obs--99 %

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