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- PDB-5f1z: Structure of TYK2 with inhibitor 16: 3-azanyl-5-[(2~{S})-3-methyl... -

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Basic information

Entry
Database: PDB / ID: 5f1z
TitleStructure of TYK2 with inhibitor 16: 3-azanyl-5-[(2~{S})-3-methylbutan-2-yl]-7-[1-methyl-5-(2-oxidanylpropan-2-yl)pyrazol-3-yl]-1~{H}-pyrazolo[4,3-c]pyridin-4-one
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / complex / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-35 Signalling ...type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / growth hormone receptor binding / positive regulation of natural killer cell proliferation / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / Interleukin-6 signaling / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / 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) / Evasion by RSV of host interferon responses / non-specific protein-tyrosine kinase / positive regulation of receptor signaling pathway via JAK-STAT / non-membrane spanning protein tyrosine kinase activity / Signaling by ALK fusions and activated point mutants / Inactivation of CSF3 (G-CSF) signaling / cytoplasmic side of plasma membrane / cellular response to virus / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / positive regulation of type II interferon production / Interferon alpha/beta signaling / 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 / 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 / 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-5U3 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.65 Å
AuthorsSkene, R.J.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors.
Authors: Yogo, T. / Nagamiya, H. / Seto, M. / Sasaki, S. / Shih-Chung, H. / Ohba, Y. / Tokunaga, N. / Lee, G.N. / Rhim, C.Y. / Yoon, C.H. / Cho, S.Y. / Skene, R. / Yamamoto, S. / Satou, Y. / Kuno, M. ...Authors: Yogo, T. / Nagamiya, H. / Seto, M. / Sasaki, S. / Shih-Chung, H. / Ohba, Y. / Tokunaga, N. / Lee, G.N. / Rhim, C.Y. / Yoon, C.H. / Cho, S.Y. / Skene, R. / Yamamoto, S. / Satou, Y. / Kuno, M. / Miyazaki, T. / Nakagawa, H. / Okabe, A. / Marui, S. / Aso, K. / Yoshida, M.
History
DepositionDec 1, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 20, 2016Group: Database references
Revision 1.2Feb 10, 2016Group: Database references
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2032
Polymers34,8451
Non-polymers3581
Water2,792155
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.805, 47.805, 476.248
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-1431-

HOH

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Components

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


Mass: 34844.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: unidentified baculovirus
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-5U3 / 3-azanyl-5-[(2~{S})-3-methylbutan-2-yl]-7-[1-methyl-5-(2-oxidanylpropan-2-yl)pyrazol-3-yl]-1~{H}-pyrazolo[4,3-c]pyridin-4-one


Mass: 358.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H26N6O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 155 / 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: 2.25 Å3/Da / Density % sol: 45.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 15% PEG 5000 MME, and 100 mM Sodium Citrate (pH 6.0)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 8, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionRedundancy: 6.3 % / Number: 92057 / Rmerge(I) obs: 0.127 / Χ2: 1.03 / D res high: 2.35 Å / D res low: 50 Å / Num. obs: 14704 / % possible obs: 99
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
6.375010.0680.9946
5.066.3710.0971.0246.9
4.425.0610.0820.9936.7
4.024.4210.0770.9866.5
3.734.0210.0790.9986.4
3.513.7310.0880.9966.7
3.333.5110.11.0126.6
3.193.3310.1541.0636.9
3.073.1910.1671.0297
2.963.0710.1911.0647.1
2.872.9610.2381.1367.1
2.792.8710.2921.0757.3
2.712.7910.3341.0717.4
2.652.7110.351.0997
2.592.6510.4481.136
2.532.5910.4441.0615.2
2.482.5310.4410.9724.9
2.432.4810.4810.9374.8
2.392.4310.5070.874
2.352.3910.5510.9044
ReflectionResolution: 2.35→50 Å / Num. obs: 14704 / % possible obs: 99 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.127 / Χ2: 1.03 / Net I/av σ(I): 10.951 / Net I/σ(I): 7.1 / Num. measured all: 92057
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.35-2.3940.5516600.90494.6
2.39-2.4340.5076650.8795.1
2.43-2.484.80.4816810.93796.2
2.48-2.534.90.4416820.97297.6
2.53-2.595.20.4447071.06199.4
2.59-2.6560.4487371.1398.8
2.65-2.7170.356691.09999.4
2.71-2.797.40.3347411.07199.7
2.79-2.877.30.2926901.075100
2.87-2.967.10.2387611.136100
2.96-3.077.10.1916971.06499.9
3.07-3.1970.1677411.02999.9
3.19-3.336.90.1547151.063100
3.33-3.516.60.17451.01299.7
3.51-3.736.70.0887430.99699.6
3.73-4.026.40.0797520.99899.7
4.02-4.426.50.0777550.986100
4.42-5.066.70.0827890.993100
5.06-6.376.90.0978151.024100
6.37-5060.0689590.99499.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.49 Å41.24 Å
Translation6.49 Å41.24 Å

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
PHASER2.5.1phasing
REFMACrefinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→30 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.818 / WRfactor Rfree: 0.31 / WRfactor Rwork: 0.216 / FOM work R set: 0.7922 / SU B: 29.827 / SU ML: 0.276 / SU R Cruickshank DPI: 2.9907 / SU Rfree: 0.416 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 2.991 / ESU R Free: 0.416 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.31 514 4.9 %RANDOM
Rwork0.216 ---
obs0.2201 10006 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 82.07 Å2 / Biso mean: 32.71 Å2 / Biso min: 7.67 Å2
Baniso -1Baniso -2Baniso -3
1-1.83 Å20.92 Å20 Å2
2--1.83 Å20 Å2
3----2.75 Å2
Refinement stepCycle: final / Resolution: 2.65→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2293 0 26 155 2474
Biso mean--30.25 30.25 -
Num. residues----281
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0192385
X-RAY DIFFRACTIONr_bond_other_d0.0010.022235
X-RAY DIFFRACTIONr_angle_refined_deg1.0341.983232
X-RAY DIFFRACTIONr_angle_other_deg0.70235159
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4085278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.94723.304112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.9315413
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5741515
X-RAY DIFFRACTIONr_chiral_restr0.0580.2342
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212638
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02553
LS refinement shellResolution: 2.65→2.718 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.407 30 -
Rwork0.257 664 -
all-694 -
obs--99.14 %
Refinement TLS params.Method: refined / Origin x: -21.464 Å / Origin y: 16.157 Å / Origin z: 492.21 Å
111213212223313233
T0.0439 Å20.0058 Å2-0.0071 Å2-0.0039 Å2-0.0036 Å2--0.0964 Å2
L0.756 °20.0589 °20.5635 °2-0.7045 °20.2248 °2--2.8657 °2
S-0.006 Å °0.0412 Å °0.0186 Å °-0.1552 Å °-0.027 Å °-0.0049 Å °-0.1921 Å °0.0379 Å °0.0331 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A886 - 1177
2X-RAY DIFFRACTION1A1200
3X-RAY DIFFRACTION1A1301 - 1455

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