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- PDB-8s98: Crystal structure of the TYK2 pseudokinase domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 8s98
TitleCrystal structure of the TYK2 pseudokinase domain in complex with compound 8
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / TYK2 / pseudokinase / JH2 / immunology
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
Similarity search - Domain/homology
Chem-ZRU / Hydrogenase-2 large chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsToms, A.V. / Leit, S. / Greenwood, J.R. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N. / Cartwright, M. ...Toms, A.V. / Leit, S. / Greenwood, J.R. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N. / Cartwright, M. / Collis, A. / Feng, S. / Ghanakota, P. / Harriman, G.C. / Hosagrahara, V. / Kaila, N. / Kapeller, R. / Rafi, S. / Romero, D.L. / Tarantino, P. / Timaniya, J. / Wester, R.T. / Westlin, W. / Srivastava, B. / Miao, W. / Tummino, P. / McElwee, J.J. / Edmondson, S.D. / Massee, C.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.
Authors: Leit, S. / Greenwood, J. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N.A. / Cartwright, M. / Collis, A. / Feng, S. / Ghanakota, P. / Harriman, G.C. / ...Authors: Leit, S. / Greenwood, J. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N.A. / Cartwright, M. / Collis, A. / Feng, S. / Ghanakota, P. / Harriman, G.C. / Hosagrahara, V. / Kaila, N. / Kapeller, R. / Rafi, S.B. / Romero, D.L. / Tarantino, P.M. / Timaniya, J. / Toms, A.V. / Wester, R.T. / Westlin, W. / Srivastava, B. / Miao, W. / Tummino, P. / McElwee, J.J. / Edmondson, S.D. / Masse, C.E.
History
DepositionMar 27, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.3Oct 9, 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
B: Non-receptor tyrosine-protein kinase TYK2
C: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,0736
Polymers99,0133
Non-polymers1,0603
Water11,259625
1
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3582
Polymers33,0041
Non-polymers3531
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)33,3582
Polymers33,0041
Non-polymers3531
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3582
Polymers33,0041
Non-polymers3531
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.108, 112.602, 156.856
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 33004.441 Da / Num. of mol.: 3
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-ZRU / (8S)-N-cyclopropyl-5-[(2-methoxypyridin-3-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 353.378 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C17H19N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 625 / 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: 2.15 Å3/Da / Density % sol: 42.67 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: The purified protein was used in crystallization trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallization conditions identified using ...Details: The purified protein was used in crystallization trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallization conditions identified using literature data. Conditions initially obtained have been optimised using standard strategies, systematically varying parameters critically influencing crystallization, such as temperature, protein concentration, drop ratio, and others. These conditions were also refined by systematically varying pH or precipitant concentrations.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 20, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.87→91.47 Å / Num. obs: 68019 / % possible obs: 95.2 % / Redundancy: 4.3 % / Rrim(I) all: 0.149 / Rsym value: 0.13 / Net I/σ(I): 10.92
Reflection shellResolution: 1.87→2.12 Å / Redundancy: 4.1 % / Mean I/σ(I) obs: 3.55 / Num. unique obs: 21481 / Rrim(I) all: 0.504 / Rsym value: 0.445 / % possible all: 97.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XSCALEdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.87→47.47 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.897 / SU B: 9.676 / SU ML: 0.15 / Cross valid method: THROUGHOUT / ESU R: 0.183 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27367 2213 3.3 %RANDOM
Rwork0.22454 ---
obs0.22617 65806 95.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.432 Å2
Baniso -1Baniso -2Baniso -3
1-0.66 Å20 Å20 Å2
2--1.03 Å2-0 Å2
3----1.69 Å2
Refinement stepCycle: 1 / Resolution: 1.87→47.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6092 0 78 625 6795
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0136419
X-RAY DIFFRACTIONr_bond_other_d0.0020.0156043
X-RAY DIFFRACTIONr_angle_refined_deg1.7781.6628731
X-RAY DIFFRACTIONr_angle_other_deg1.421.58613903
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5485788
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.67720.901333
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.234151044
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7291553
X-RAY DIFFRACTIONr_chiral_restr0.0850.2809
X-RAY DIFFRACTIONr_gen_planes_refined0.010.027227
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021476
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5140.5483149
X-RAY DIFFRACTIONr_mcbond_other0.5140.5473148
X-RAY DIFFRACTIONr_mcangle_it0.9330.8123938
X-RAY DIFFRACTIONr_mcangle_other0.9330.8133939
X-RAY DIFFRACTIONr_scbond_it0.4730.5943270
X-RAY DIFFRACTIONr_scbond_other0.4720.5943271
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.7660.8734785
X-RAY DIFFRACTIONr_long_range_B_refined5.3647.5777363
X-RAY DIFFRACTIONr_long_range_B_other5.2166.9047221
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.87→1.919 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 151 -
Rwork0.326 4836 -
obs--95.63 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3255-0.20720.20950.7868-0.51561.85560.07850.2985-0.0482-0.2214-0.0244-0.03510.07470.1092-0.05410.0730.00930.02330.072-0.01590.4011-29.332-78.608-13.412
21.1431-0.51130.12441.98230.22370.86550.0045-0.17980.09560.17110.0257-0.0143-0.077-0.0713-0.03020.0308-0.00050.01010.0323-0.01710.3419-29.006-68.2966.975
32.2026-0.4427-0.35931.40090.8031.64660.00660.3687-0.1271-0.2137-0.03460.0537-0.0459-0.08670.0280.0472-0.0062-0.02030.0655-0.02640.37930.905-38.43415.695
41.0981-0.0399-0.08992.1867-0.27691.0979-0.0304-0.2115-0.08060.24650.0642-0.01190.14720.1175-0.03380.06040.0306-0.00950.05340.00380.36520.277-44.61838.014
52.5936-0.43330.67791.14080.0612.1981-0.0741-0.37750.15710.2406-0.01120.0807-0.0497-0.12410.08530.0666-0.00560.02690.0603-0.03450.3592-23.029-21.84939.766
61.2380.60140.20871.9196-0.62470.995-0.05310.22650.0312-0.21380.07040.0393-0.08570.0949-0.01730.0649-0.01530.00390.0453-0.00880.3604-23.592-15.49417.413
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A578 - 689
2X-RAY DIFFRACTION2A690 - 867
3X-RAY DIFFRACTION3B578 - 689
4X-RAY DIFFRACTION4B690 - 867
5X-RAY DIFFRACTION5C578 - 689
6X-RAY DIFFRACTION6C690 - 868

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