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- PDB-7ax4: Human TYK2 pseudokinase domain (575-869) in complex with 5-(4-Flu... -

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Basic information

Entry
Database: PDB / ID: 7ax4
TitleHuman TYK2 pseudokinase domain (575-869) in complex with 5-(4-Fluoro-phenyl)-2-ureido-thiophene-3-carboxylic acid amide.
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsSIGNALING PROTEIN / TYK2 PSEUDOKINASE TPCA-1
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 / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / Interleukin-10 signaling / MAPK1 (ERK2) activation / positive regulation of natural killer cell proliferation / 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 / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / 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 / 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 / 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 / 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
Chem-NM7 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.12 Å
AuthorsRowland, P.
CitationJournal: SLAS Discov / Year: 2021
Title: Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System.
Authors: Greenhough, L.A. / Clarke, G. / Phillipou, A.N. / Mazani, F. / Karamshi, B. / Rowe, S. / Rowland, P. / Messenger, C. / Haslam, C.P. / Bingham, R.P. / Craggs, P.D.
History
DepositionNov 9, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 21, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.2Apr 28, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.3May 5, 2021Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.4May 12, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.5May 19, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.6May 26, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.7Jun 2, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)66,6166
Polymers65,9772
Non-polymers6394
Water7,350408
1
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3083
Polymers32,9881
Non-polymers3192
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3083
Polymers32,9881
Non-polymers3192
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.600, 48.460, 121.350
Angle α, β, γ (deg.)90.000, 92.950, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 32988.441 Da / Num. of mol.: 2
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-NM7 / 2-(carbamoylamino)-5-(4-fluorophenyl)thiophene-3-carboxamide


Mass: 279.290 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H10FN3O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 408 / 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: 2.25 Å3/Da / Density % sol: 45.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 25.5% w/v PEG 4000, 0.21 M calcium chloride, 0.10 M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.97296 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97296 Å / Relative weight: 1
ReflectionResolution: 2.12→51 Å / Num. obs: 31273 / % possible obs: 93.3 % / Redundancy: 3.3 % / CC1/2: 0.991 / Rmerge(I) obs: 0.11 / Net I/σ(I): 8
Reflection shellResolution: 2.12→2.13 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.635 / Mean I/σ(I) obs: 2 / Num. unique obs: 303 / CC1/2: 0.754 / % possible all: 95

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.12→27.41 Å / Cor.coef. Fo:Fc: 0.8761 / Cor.coef. Fo:Fc free: 0.8481 / SU R Cruickshank DPI: 0.237 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.256 / SU Rfree Blow DPI: 0.194 / SU Rfree Cruickshank DPI: 0.19
RfactorNum. reflection% reflectionSelection details
Rfree0.2288 1582 5.06 %RANDOM
Rwork0.1836 ---
obs0.186 31247 92.75 %-
Displacement parametersBiso max: 133.27 Å2 / Biso mean: 32.19 Å2 / Biso min: 9.71 Å2
Baniso -1Baniso -2Baniso -3
1-13.4961 Å20 Å2-0.4728 Å2
2--5.513 Å20 Å2
3----19.0091 Å2
Refine analyzeLuzzati coordinate error obs: 0.253 Å
Refinement stepCycle: final / Resolution: 2.12→27.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4138 0 40 408 4586
Biso mean--22.27 40.51 -
Num. residues----522
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1480SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes92HARMONIC2
X-RAY DIFFRACTIONt_gen_planes656HARMONIC5
X-RAY DIFFRACTIONt_it4272HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion534SEMIHARMONIC5
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_contact5105SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4272HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5796HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3.16
X-RAY DIFFRACTIONt_other_torsion16.9
LS refinement shellResolution: 2.12→2.19 Å / Rfactor Rfree error: 0 / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2719 119 4.14 %
Rwork0.2169 2752 -
all0.2193 2871 -
obs--93.1 %
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)
11.20980.2114-0.05330.9630.10750.74270.0163-0.12720.11470.0748-0.04540.058-0.0035-0.02490.0292-0.01610.00330.0014-0.0004-0.0185-0.15924.142-11.049812.831
21.3123-0.0510.24560.71330.18280.79370.01750.1385-0.0593-0.0708-0.0348-0.010.0170.03510.0173-0.00880.00230.02760.0055-0.0092-0.161846.31727.720247.7743
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A579 - 868
2X-RAY DIFFRACTION2{ B|* }B579 - 868

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