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- PDB-4gih: Tyk2 (JH1) in complex with 2,6-DICHLORO-N-{2-[(CYCLOPROPYLCARBONY... -

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Basic information

Entry
Database: PDB / ID: 4gih
TitleTyk2 (JH1) in complex with 2,6-DICHLORO-N-{2-[(CYCLOPROPYLCARBONYL)AMINO]PYRIDIN-4-YL}BENZAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Tyrosine Kinase / Kinase / ATP Binding / Inhibitor / 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 / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...: / 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 / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-0X5 / Hydrogenase-2 large chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsUltsch, M.H.
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 8, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Database references
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Sep 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,0992
Polymers34,7491
Non-polymers3501
Water2,144119
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.165, 74.378, 105.855
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-0X5 / 2,6-dichloro-N-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}benzamide


Mass: 350.199 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13Cl2N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 39.96 %
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

DiffractionMean temperature: 173 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 14, 2012
RadiationMonochromator: Liquid nitrogen-cooled double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2→25 Å / Num. all: 19180 / Num. obs: 19107 / % possible obs: 95.7 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.9 % / Biso Wilson estimate: 34.91 Å2 / Rsym value: 0.082 / Net I/σ(I): 19.29
Reflection shellResolution: 2→2.07 Å / Redundancy: 5.1 % / Mean I/σ(I) obs: 4.1 / Num. unique all: 1504 / Rsym value: 0.334 / % possible all: 77.5

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Processing

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

3nz0


Resolution: 2→24.93 Å / Cor.coef. Fo:Fc: 0.9541 / Cor.coef. Fo:Fc free: 0.9434 / SU R Cruickshank DPI: 0.198 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2169 983 5.14 %RANDOM
Rwork0.1878 ---
all0.2169 19180 --
obs0.1893 19107 95.62 %-
Displacement parametersBiso mean: 45.19 Å2
Baniso -1Baniso -2Baniso -3
1-0.7143 Å20 Å20 Å2
2--0.4279 Å20 Å2
3----1.1422 Å2
Refine analyzeLuzzati coordinate error obs: 0.255 Å
Refinement stepCycle: LAST / Resolution: 2→24.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2335 0 23 119 2477
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082429HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.973291HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d840SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes54HARMONIC2
X-RAY DIFFRACTIONt_gen_planes355HARMONIC5
X-RAY DIFFRACTIONt_it2429HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion19.03
X-RAY DIFFRACTIONt_chiral_improper_torsion294SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2830SEMIHARMONIC4
LS refinement shellResolution: 2→2.11 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2168 118 5.32 %
Rwork0.2055 2102 -
all0.2061 2220 -
obs--95.62 %
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)
13.9612-1.6988-0.5642.45340.43614.25670.0814-0.4121-0.05210.00570.124-0.19720.0835-0.0708-0.2053-0.0220.009-0.0647-0.13180.0144-0.0653-4.6113-16.2488-8.5956
20.8911-0.96740.50082.2301-0.33411.77860.0559-0.1862-0.14470.28270.11590.18680.1688-0.001-0.1718-0.0935-0.0508-0.0089-0.10830.0447-0.0528-11.8436-7.1646-11.4839
32.228-0.338-0.25325.83890.11841.6158-0.0575-0.2960.1280.3617-0.02140.1523-0.04410.10940.0788-0.1086-0.006-0.0045-0.03980.0181-0.0816-10.57467.3113-11.8491
42.1237-0.42240.59282.02660.03760.67680.04160.10110.198-0.0377-0.08950.0797-0.00840.04890.0479-0.09540.01370.0038-0.08380.0312-0.0332-12.975612.7958-24.7516
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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