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- PDB-8s99: Crystal structure of the TYK2 pseudokinase domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 8s99
TitleCrystal structure of the TYK2 pseudokinase domain in complex with compound 11
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / TYK2 / pseudokinase / JH2 / immunology
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-27 signaling ...type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / 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 / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / Interleukin-6 signaling / MAPK3 (ERK1) activation / 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 / growth hormone receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / 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 / Evasion by RSV of host interferon responses / 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 / 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 / cytoplasm / cytosol
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
ACETATE ION / Chem-ZS3 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 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

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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)100,87215
Polymers98,9653
Non-polymers1,90712
Water12,088671
1
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6245
Polymers32,9881
Non-polymers6364
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)33,6245
Polymers32,9881
Non-polymers6364
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)33,6245
Polymers32,9881
Non-polymers6364
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.209, 112.715, 157.448
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: 32988.441 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-ZS3 / (8S)-N-[(1R,2S)-2-fluorocyclopropyl]-5-{[(1M,2'M)-3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl]amino}-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 452.417 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H18F2N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 671 / 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: 2.16 Å3/Da / Density % sol: 43.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion
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 optimized 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: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.71→91.65 Å / Num. obs: 92953 / % possible obs: 99.2 % / Redundancy: 3.2 % / Rrim(I) all: 0.085 / Rsym value: 0.071 / Net I/σ(I): 11.32
Reflection shellResolution: 1.71→1.96 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 2.96 / Num. unique obs: 30817 / Rrim(I) all: 0.536 / Rsym value: 0.447 / % possible all: 99.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.71→47.62 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.941 / SU B: 5.22 / SU ML: 0.085 / Cross valid method: THROUGHOUT / ESU R: 0.113 / ESU R Free: 0.111 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22541 3022 3.3 %RANDOM
Rwork0.19004 ---
obs0.19115 89919 99.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.303 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å20 Å20 Å2
2--0.93 Å2-0 Å2
3----0.54 Å2
Refinement stepCycle: 1 / Resolution: 1.71→47.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6203 0 135 671 7009
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0136733
X-RAY DIFFRACTIONr_bond_other_d0.0010.0156318
X-RAY DIFFRACTIONr_angle_refined_deg1.4261.6749180
X-RAY DIFFRACTIONr_angle_other_deg1.3671.5914542
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1535834
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.99820.734354
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.942151095
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.871559
X-RAY DIFFRACTIONr_chiral_restr0.0710.2845
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.027716
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021579
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_it0.7291.2093279
X-RAY DIFFRACTIONr_mcbond_other0.7251.2063275
X-RAY DIFFRACTIONr_mcangle_it1.2981.7964130
X-RAY DIFFRACTIONr_mcangle_other1.2981.7974131
X-RAY DIFFRACTIONr_scbond_it0.721.2853454
X-RAY DIFFRACTIONr_scbond_other0.721.2853455
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.1931.8955033
X-RAY DIFFRACTIONr_long_range_B_refined5.02515.1347751
X-RAY DIFFRACTIONr_long_range_B_other4.78714.3587578
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.71→1.754 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 230 -
Rwork0.337 6490 -
obs--98.61 %
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)
12.1453-0.2032-0.40111.22760.461.3728-0.01720.2864-0.1131-0.1962-0.02370.0854-0.0345-0.0380.04090.05680.0052-0.02120.0443-0.03040.08990.87-38.26815.608
21.2247-0.1142-0.1671.6398-0.01161.095-0.0225-0.2015-0.15410.21480.0432-0.04020.1560.1136-0.02070.07380.019-0.02050.0510.00440.10380.182-44.73438.102
32.7749-0.26560.2440.95950.15521.3575-0.0556-0.30570.11640.17310.01490.0543-0.0201-0.06590.04070.0716-0.00240.01590.0529-0.03190.0788-23.093-22.22440.075
41.06630.51760.24311.7766-0.35931.0203-0.06030.19340.1105-0.19630.04210.0242-0.12410.07330.01830.0813-0.01820.00860.0517-0.00580.1044-23.832-15.38217.504
51.498-0.16140.320.7912-0.29891.3480.03490.2495-0.0047-0.1995-0.0466-0.05840.04380.05390.01170.08410.01890.01730.0441-0.00150.0809-29.31-78.907-13.501
60.949-0.37920.14841.72080.06410.8172-0.005-0.16460.11260.14680.0067-0.0324-0.1032-0.0717-0.00170.06490.00430.01320.0387-0.01210.0917-29.024-68.2557.207
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A578 - 689
2X-RAY DIFFRACTION2A690 - 868
3X-RAY DIFFRACTION3B579 - 689
4X-RAY DIFFRACTION4B690 - 867
5X-RAY DIFFRACTION5C578 - 689
6X-RAY DIFFRACTION6C690 - 867

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