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- PDB-6x8f: Crystal structure of TYK2 with Compound 11 -

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Basic information

Entry
Database: PDB / ID: 6x8f
TitleCrystal structure of TYK2 with Compound 11
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / kinase
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
Similarity search - Domain/homology
Chem-UWP / Hydrogenase-2 large chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsVajdos, F.F. / Knafels, J.D.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.
Authors: Gerstenberger, B.S. / Ambler, C. / Arnold, E.P. / Banker, M.E. / Brown, M.F. / Clark, J.D. / Dermenci, A. / Dowty, M.E. / Fensome, A. / Fish, S. / Hayward, M.M. / Hegen, M. / Hollingshead, B. ...Authors: Gerstenberger, B.S. / Ambler, C. / Arnold, E.P. / Banker, M.E. / Brown, M.F. / Clark, J.D. / Dermenci, A. / Dowty, M.E. / Fensome, A. / Fish, S. / Hayward, M.M. / Hegen, M. / Hollingshead, B.D. / Knafels, J.D. / Lin, D.W. / Lin, T.H. / Owen, D.R. / Saiah, E. / Sharma, R. / Vajdos, F.F. / Xing, L. / Yang, X. / Yang, X. / Wright, S.W.
History
DepositionJun 1, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 25, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 9, 2020Group: 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 18, 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 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
C: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,9844
Polymers73,1012
Non-polymers8832
Water3,189177
1
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9922
Polymers36,5511
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
C: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9922
Polymers36,5511
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.275, 36.098, 100.256
Angle α, β, γ (deg.)90.000, 91.150, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 36550.570 Da / Num. of mol.: 2 / 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-UWP / [3-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1H-pyrazol-1-yl}-1-(2,2,2-trifluoroethyl)azetidin-3-yl]acetonitrile


Mass: 441.412 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H18F3N9 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 177 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.84 Å3/Da / Density % sol: 33.09 % / Mosaicity: 0.46 °
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: Mar 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→74.26 Å / Num. obs: 24732 / % possible obs: 83 % / Redundancy: 2.9 % / Biso Wilson estimate: 26.94 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.057 / Rrim(I) all: 0.101 / Net I/σ(I): 161.4 / Num. measured all: 70912 / Scaling rejects: 17
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.15-2.261.90.449408621000.6980.3740.58826.448.9
6.78-74.2630.02429999950.9990.0160.029496.196.8

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.2.8data scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LXP

3lxp


Resolution: 2.15→50.12 Å / Cor.coef. Fo:Fc: 0.8942 / Cor.coef. Fo:Fc free: 0.8568 / SU R Cruickshank DPI: 0.704 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.721 / SU Rfree Blow DPI: 0.281 / SU Rfree Cruickshank DPI: 0.284
RfactorNum. reflection% reflectionSelection details
Rfree0.2549 1110 5.03 %RANDOM
Rwork0.2052 ---
obs0.2077 22072 74.6 %-
Displacement parametersBiso max: 133.39 Å2 / Biso mean: 41.27 Å2 / Biso min: 6.77 Å2
Baniso -1Baniso -2Baniso -3
1-9.3608 Å20 Å27.0586 Å2
2--5.7624 Å20 Å2
3----15.1232 Å2
Refine analyzeLuzzati coordinate error obs: 0.314 Å
Refinement stepCycle: final / Resolution: 2.15→50.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4652 0 64 177 4893
Biso mean--30.92 35.34 -
Num. residues----573
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1672SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes108HARMONIC2
X-RAY DIFFRACTIONt_gen_planes770HARMONIC5
X-RAY DIFFRACTIONt_it4894HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion581SEMIHARMONIC5
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_contact5611SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4894HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6674HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion20.6
LS refinement shellResolution: 2.15→2.25 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.3744 68 4.59 %
Rwork0.2634 1415 -
all0.2685 1483 -
obs--74.6 %

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