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- PDB-5wal: Identification of an imidazopyridine scaffold to generate potent ... -

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Basic information

Entry
Database: PDB / ID: 5wal
TitleIdentification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Tyk2 / Kinase / Inhibitor / 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-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / 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-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of NK T cell proliferation / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / extrinsic component of cytoplasmic side of plasma membrane / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-10 signaling / positive regulation of interleukin-17 production / positive regulation of natural killer cell proliferation / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / 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 / non-specific protein-tyrosine kinase / cellular response to virus / positive regulation of protein localization to nucleus / cytoplasmic side of plasma membrane / Interferon alpha/beta signaling / positive regulation of type II interferon production / Signaling by ALK fusions and activated point mutants / cytokine-mediated signaling pathway / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / cell population proliferation / receptor complex / intracellular signal transduction / protein phosphorylation / immune response / 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 / SH2 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 / SH2 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-9ZS / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsUltsch, M.H. / Magnuson, S.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model.
Authors: Liang, J. / Van Abbema, A. / Balazs, M. / Barrett, K. / Berezhkovsky, L. / Blair, W.S. / Chang, C. / Delarosa, D. / DeVoss, J. / Driscoll, J. / Eigenbrot, C. / Goodacre, S. / Ghilardi, N. / ...Authors: Liang, J. / Van Abbema, A. / Balazs, M. / Barrett, K. / Berezhkovsky, L. / Blair, W.S. / Chang, C. / Delarosa, D. / DeVoss, J. / Driscoll, J. / Eigenbrot, C. / Goodacre, S. / Ghilardi, N. / MacLeod, C. / Johnson, A. / Bir Kohli, P. / Lai, Y. / Lin, Z. / Mantik, P. / Menghrajani, K. / Nguyen, H. / Peng, I. / Sambrone, A. / Shia, S. / Smith, J. / Sohn, S. / Tsui, V. / Ultsch, M. / Williams, K. / Wu, L.C. / Yang, W. / Zhang, B. / Magnuson, S.
History
DepositionJun 26, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 6, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)35,0962
Polymers34,7491
Non-polymers3471
Water1,65792
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.097, 74.301, 106.444
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
Mutation: C936A, Q969A, E971A, K972A, S1016A, C1142A, D1023N
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-9ZS / N-[2-(2,6-dichlorophenyl)-1H-imidazo[4,5-c]pyridin-4-yl]cyclopropanecarboxamide


Mass: 347.199 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12Cl2N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / 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: 40.12 % / Description: This rods
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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 15, 2012
RadiationMonochromator: Si(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.45→60.93 Å / Num. obs: 11094 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 6.4 % / Biso Wilson estimate: 42 Å2 / Rsym value: 0.128 / Net I/σ(I): 10.7
Reflection shellResolution: 2.45→2.535 Å / Redundancy: 6.8 % / Num. unique obs: 1068 / Rsym value: 0.631 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NZ0

3nz0


Resolution: 2.45→60.93 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.873 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.682 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.125 / SU Rfree Blow DPI: 0.286 / SU Rfree Cruickshank DPI: 0.282
RfactorNum. reflection% reflectionSelection details
Rfree0.243 570 5.15 %RANDOM
Rwork0.182 ---
obs0.185 11068 99.8 %-
Displacement parametersBiso mean: 37.46 Å2
Baniso -1Baniso -2Baniso -3
1-5.5024 Å20 Å20 Å2
2--6.5137 Å20 Å2
3----12.0161 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 2.45→60.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2322 0 23 95 2440
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092477HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043363HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d863SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes56HARMONIC2
X-RAY DIFFRACTIONt_gen_planes366HARMONIC5
X-RAY DIFFRACTIONt_it2477HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.77
X-RAY DIFFRACTIONt_other_torsion19.66
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion300SEMIHARMONIC5
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_contact2884SEMIHARMONIC4
LS refinement shellResolution: 2.45→2.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.275 125 4.84 %
Rwork0.196 2456 -
all0.2 2581 -
obs--99.73 %
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)
10.6097-0.0286-0.36261.7426-1.25371.805-0.01070.16620.0603-0.23470.036-0.03780.0360.1394-0.0253-0.0185-0.0047-0.0038-0.06210.0014-0.0205-7.53612.24476.2878
20.820.24740.08412.1792-0.05520.55190.02920.0166-0.0257-0.081-0.0110.12040.0444-0.004-0.0182-0.0822-0.0088-0.0066-0.0787-0.007-0.0085-12.4497-8.380420.9998
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|890 - A|982 }A890 - 982
2X-RAY DIFFRACTION2{ A|983 - A|1177 A|1201 - A|1201 }A983 - 1177
3X-RAY DIFFRACTION2{ A|983 - A|1177 A|1201 - A|1201 }A1201

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