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- PDB-4gvj: Tyk2 (JH1) in complex with adenosine di-phosphate -

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Basic information

Entry
Database: PDB / ID: 4gvj
TitleTyk2 (JH1) in complex with adenosine di-phosphate
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsHYDROLASE / Kinase
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 / 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
ADENOSINE-5'-DIPHOSPHATE / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsLiang, J. / Abbema, A.V. / Bao, L. / Barrett, K. / Beresini, M. / Berezhkovskiy, L. / Blair, W. / Chang, C. / Driscoll, J. / Eigenbrot, C. ...Liang, J. / Abbema, A.V. / Bao, L. / Barrett, K. / Beresini, M. / Berezhkovskiy, L. / Blair, W. / Chang, C. / Driscoll, J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Halladay, J. / Johnson, A. / Kohli, P.B. / Lai, Y. / Liimatta, M. / Mantik, P. / Menghrajani, K. / Murray, J. / Sambrone, A. / Shao, Y. / Shia, S. / Shin, Y. / Smith, J. / Sohn, S. / Stanley, M. / Tsui, V. / Ultsch, M. / Wu, L. / Zhang, B. / Magnuson, S.
CitationJournal: Eur.J.Med.Chem. / Year: 2013
Title: Lead identification of novel and selective TYK2 inhibitors.
Authors: Liang, J. / Tsui, V. / Van Abbema, A. / Bao, L. / Barrett, K. / Beresini, M. / Berezhkovskiy, L. / Blair, W.S. / Chang, C. / Driscoll, J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / ...Authors: Liang, J. / Tsui, V. / Van Abbema, A. / Bao, L. / Barrett, K. / Beresini, M. / Berezhkovskiy, L. / Blair, W.S. / Chang, C. / Driscoll, J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Halladay, J. / Johnson, A. / Kohli, P.B. / Lai, Y. / Liimatta, M. / Mantik, P. / Menghrajani, K. / Murray, J. / Sambrone, A. / Xiao, Y. / Shia, S. / Shin, Y. / Smith, J. / Sohn, S. / Stanley, M. / Ultsch, M. / Zhang, B. / Wu, L.C. / Magnuson, S.
History
DepositionAug 30, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 8, 2016Group: Structure summary
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)35,2264
Polymers34,7501
Non-polymers4763
Water1,60389
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.326, 74.051, 105.321
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: 34749.723 Da / Num. of mol.: 1 / Fragment: Kinase domain, UNP residues 885-1176 / Mutation: C936A, Q969A, E971A, K972A, C1142A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Cell line (production host): Tni / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 89 / 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: 2.04 Å3/Da / Density % sol: 39.65 %
Crystal growTemperature: 291 K / pH: 6.5
Details: 20-30% w/v PEG 3350, 0.2M Mg sulfate, 0.1M MES , pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 16, 2011 / Details: MIRRORS- BERYLLIUM LENSES
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.03→50 Å / Num. obs: 19030 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 6 % / Biso Wilson estimate: 36.44 Å2 / Rsym value: 0.69 / Net I/σ(I): 25.5
Reflection shellResolution: 2.03→2.1 Å / Redundancy: 5.6 % / Mean I/σ(I) obs: 2.7 / Rsym value: 0.581 / % possible all: 98.8

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
BUSTER2.11.2refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3NZ0

3nz0


Resolution: 2.03→34.93 Å / Cor.coef. Fo:Fc: 0.9494 / Cor.coef. Fo:Fc free: 0.9342 / SU R Cruickshank DPI: 0.197 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2311 1030 5.41 %RANDOM
Rwork0.1879 ---
obs0.1902 19030 99.86 %-
all-19115 --
Displacement parametersBiso mean: 46.56 Å2
Baniso -1Baniso -2Baniso -3
1--10.9822 Å20 Å20 Å2
2--4.8398 Å20 Å2
3---6.1424 Å2
Refine analyzeLuzzati coordinate error obs: 0.274 Å
Refinement stepCycle: LAST / Resolution: 2.03→34.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 29 89 2470
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012449HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043323HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d847SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes371HARMONIC5
X-RAY DIFFRACTIONt_it2449HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion20.03
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion299SEMIHARMONIC5
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_contact2799SEMIHARMONIC4
LS refinement shellResolution: 2.03→2.14 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2482 154 5.7 %
Rwork0.2173 2549 -
all0.2192 2703 -
obs--99.86 %
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)
14.477-1.22270.04320.62021.65974.84510.015-0.23940.0090.12390.08040.3137-0.1926-0.1593-0.09540.02320.00880.0412-0.14320.006-0.08873.82617.0454-8.8231
20.8877-0.4318-0.27932.26140.4271.82030.0413-0.2190.11140.41450.0507-0.222-0.30730.017-0.092-0.0298-0.0328-0.0208-0.0791-0.0194-0.066311.99647.6641-11.6438
32.8754-0.08780.06635.05360.41271.7769-0.0465-0.3432-0.26830.52870.0856-0.10590.0576-0.0891-0.0391-0.07110.0063-0.0071-0.04130.0225-0.082110.7767-6.9338-11.911
42.5855-0.75640.05612.4192-0.40780.7510.02470.1388-0.2056-0.0879-0.0723-0.17060.07860.03060.0476-0.1190.01830.0094-0.0815-0.0207-0.03113.0804-12.1303-24.7976
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|890 - A|916 }A890 - 916
2X-RAY DIFFRACTION2{ A|917 - A|1017 }A917 - 1017
3X-RAY DIFFRACTION3{ A|1018 - A|1076 }A1018 - 1076
4X-RAY DIFFRACTION4{ A|1077 - A|1177 }A1077 - 1177

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