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- PDB-7uyt: Crystal structure of TYK2 kinase domain in complex with compound 25 -

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Basic information

Entry
Database: PDB / ID: 7uyt
TitleCrystal structure of TYK2 kinase domain in complex with compound 25
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / non-receptor tyrosine-protein kinase 2 / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


hydrogenase (acceptor) / hydrogenase (acceptor) activity / ferredoxin hydrogenase activity / nickel cation binding / plasma membrane
Similarity search - Function
: / Nickel-dependent hydrogenases large subunit signature 2. / Nickel-dependent hydrogenases large subunit signature 1. / Nickel-dependent hydrogenase, large subunit, nickel binding site / Nickel-dependent hydrogenase, large subunit / Nickel-dependent hydrogenase / [NiFe]-hydrogenase, large subunit
Similarity search - Domain/homology
Chem-OV5 / Hydrogenase-2 large chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.14 Å
AuthorsToms, A.V. / Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. ...Toms, A.V. / Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Shelley, M. / Wester, R.T. / Westlin, W. / Mc Elwee, J.J. / Miao, W. / Edmondson, S.D. / Massee, C.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.
Authors: Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Toms, A.V. / Shelley, M. / Wester, ...Authors: Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Toms, A.V. / Shelley, M. / Wester, R.T. / Westlin, W. / McElwee, J.J. / Miao, W. / Edmondson, S.D. / Masse, C.E.
History
DepositionMay 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification

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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)34,0672
Polymers33,6431
Non-polymers4241
Water1,13563
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)35.975, 73.829, 104.771
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 33643.371 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
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-OV5 / 6-{[(2M)-2-(2-chloro-6-fluorophenyl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-4-yl]amino}-N-ethylpyridine-3-carboxamide


Mass: 423.828 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H15ClFN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.15 Å3/Da / Density % sol: 42.75 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: Crystals of human TYK2 in complex with the ligand were prepared according to established protocols

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 1, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.14→42.76 Å / Num. obs: 15450 / % possible obs: 96.2 % / Redundancy: 3.1 % / Rmerge(I) obs: 0.072 / Net I/σ(I): 12.31
Reflection shellResolution: 2.14→2.39 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.438 / Mean I/σ(I) obs: 2.48 / Num. unique obs: 4314 / Rrim(I) all: 0.525 / Rsym value: 0.438 / % possible all: 97.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.14→42.76 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.903 / SU B: 21.321 / SU ML: 0.261 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.367 / ESU R Free: 0.265 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2929 1520 9.8 %RANDOM
Rwork0.2392 ---
obs0.2447 13930 96.26 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 102.92 Å2 / Biso mean: 46.775 Å2 / Biso min: 19.33 Å2
Baniso -1Baniso -2Baniso -3
1--1.54 Å2-0 Å2-0 Å2
2---0.08 Å20 Å2
3---1.63 Å2
Refinement stepCycle: final / Resolution: 2.14→42.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2164 0 30 63 2257
Biso mean--41.79 39.28 -
Num. residues----278
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0132265
X-RAY DIFFRACTIONr_bond_other_d0.0010.0152038
X-RAY DIFFRACTIONr_angle_refined_deg1.4881.6643086
X-RAY DIFFRACTIONr_angle_other_deg1.2341.5854661
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7365276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.46721.604106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.67115336
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4141512
X-RAY DIFFRACTIONr_chiral_restr0.0630.2285
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022552
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02529
LS refinement shellResolution: 2.14→2.196 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 117 -
Rwork0.365 1004 -
all-1121 -
obs--97.82 %
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)
13.8325-2.3529-0.95064.25821.90833.3078-0.0352-0.75210.25810.47480.1654-0.0569-0.3084-0.113-0.13020.4006-0.0467-0.02650.1973-0.05390.48647.73412.406-6.225
23.07-0.26290.22793.8237-0.12541.06530.0498-0.0812-0.05810.0391-0.104-0.12290.04880.02530.05420.0664-0.00140.01370.00620.00530.338212.818-8.326-20.971
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A890 - 979
2X-RAY DIFFRACTION2A983 - 1177

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