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- PDB-4gj3: Tyk2 (JH1) in complex with 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2... -

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Basic information

Entry
Database: PDB / ID: 4gj3
TitleTyk2 (JH1) in complex with 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / ATP Binding / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / Interleukin-12 signaling ...type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / 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 / extrinsic component of plasma membrane / Other interleukin signaling / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / Interleukin-6 signaling / MAPK3 (ERK1) activation / extrinsic component of cytoplasmic side of plasma membrane / 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 / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / positive regulation of receptor signaling pathway via JAK-STAT / Inactivation of CSF3 (G-CSF) signaling / cellular response to virus / Evasion by RSV of host interferon responses / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / cytoplasmic side of plasma membrane / positive regulation of type II interferon production / Interferon alpha/beta signaling / 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 / 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 ...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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-0XP / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsUltsch, M.H.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors.
Authors: Liang, J. / van Abbema, A. / Balazs, M. / Barrett, K. / Berezhkovsky, L. / Blair, W. / Chang, C. / Delarosa, D. / Devoss, J. / Driscoll, J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / ...Authors: Liang, J. / van Abbema, A. / Balazs, M. / Barrett, K. / Berezhkovsky, L. / Blair, W. / Chang, C. / Delarosa, D. / Devoss, J. / Driscoll, J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Halladay, J. / Johnson, A. / Kohli, P.B. / Lai, Y. / Liu, Y. / Lyssikatos, J. / Mantik, P. / Menghrajani, K. / Murray, J. / Peng, I. / Sambrone, A. / Shia, S. / Shin, Y. / Smith, J. / Sohn, S. / Tsui, V. / Ultsch, M. / Wu, L.C. / Xiao, Y. / Yang, W. / Young, J. / Zhang, B. / Zhu, B.Y. / Magnuson, S.
History
DepositionAug 9, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2013Group: Database references
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 / 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 / _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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,1422
Polymers34,7491
Non-polymers3931
Water1,18966
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.229, 74.203, 105.891
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: 34748.734 Da / Num. of mol.: 1 / Fragment: Kinase domain, UNP residues 885-1176 / Mutation: C936A,Q969A,E971A,K972A,D1023N,C1142A
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-0XP / 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide


Mass: 393.199 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H11Cl2FN4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 2.05 Å3/Da / Density % sol: 39.94 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20-25%(w/v) PEG3350 and 0.2M Mg sulfate, 0.1M MES pH6.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 11, 2012
RadiationMonochromator: Side scattering bent cube-root I-beam single crystal; asymmetric cut 4.965 degs
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.5→35.3 Å / Num. obs: 9108 / % possible obs: 88.2 % / Observed criterion σ(I): 2 / Redundancy: 4.5 % / Biso Wilson estimate: 49.61 Å2 / Rmerge(I) obs: 0.8 / Net I/σ(I): 16.3
Reflection shellResolution: 2.5→2.63 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.435 / Mean I/σ(I) obs: 4.2 / Num. unique all: 1329 / % possible all: 90.1

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Processing

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

3nz0


Resolution: 2.5→34.28 Å / Cor.coef. Fo:Fc: 0.9195 / Cor.coef. Fo:Fc free: 0.8856 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2601 884 9.74 %RANDOM
Rwork0.2068 ---
all0.2117 ---
obs0.2117 9072 87 %-
Displacement parametersBiso mean: 41.29 Å2
Baniso -1Baniso -2Baniso -3
1-1.5073 Å20 Å20 Å2
2--1.7426 Å20 Å2
3----3.2499 Å2
Refine analyzeLuzzati coordinate error obs: 0.353 Å
Refinement stepCycle: LAST / Resolution: 2.5→34.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2335 0 26 66 2427
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0072427HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.953291HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d835SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes353HARMONIC5
X-RAY DIFFRACTIONt_it2427HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.11
X-RAY DIFFRACTIONt_other_torsion19.06
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2704SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.79 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2938 261 10.03 %
Rwork0.2271 2342 -
all0.2337 2603 -
obs--87 %
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)
11.9769-1.42520.51071.452-0.54174.41570.0308-0.13450.01960.03250.008-0.0984-0.04060.0043-0.03880.04420.0672-0.034-0.07860.0001-0.1775-4.5949-16.3208-8.6848
21.2485-0.68720.43042.2167-0.63792.67250.0157-0.1586-0.01470.29680.05090.04070.1243-0.0106-0.0666-0.0714-0.0317-0.0018-0.1360.0246-0.0993-11.8874-7.1966-11.5528
31.5990.4336-0.34523.8119-0.20251.10860.0346-0.02770.1820.2252-0.03310.0897-0.04810.0192-0.0015-0.0710.0153-0.0033-0.07790.0412-0.055-10.59767.2835-11.8787
41.5951-0.00730.0071.5917-0.03560.3524-0.00650.17180.1899-0.0475-0.01470.0912-0.0418-0.05340.0212-0.0810.03020.0089-0.08960.0303-0.0285-12.987212.8374-24.7142
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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