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- PDB-4gj2: Tyk2 (JH1) in complex with 2,6-dichloro-N-[2-({[(1R,2R)-2-fluoroc... -

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Basic information

Entry
Database: PDB / ID: 4gj2
TitleTyk2 (JH1) in complex with 2,6-dichloro-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


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-0XH / Hydrogenase-2 large chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,1172
Polymers34,7491
Non-polymers3681
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.149, 74.077, 106.009
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 696-1022 / Mutation: C936A,Q969A,E971A,K972A,D1023N,C1142A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: Tyk2 gene / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0XH / 2,6-dichloro-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide


Mass: 368.190 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12Cl2FN3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 39.77 %
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: 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: 2.4→37.04 Å / Num. obs: 11482 / % possible obs: 98.8 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Biso Wilson estimate: 47.22 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 13
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.489 / Mean I/σ(I) obs: 2.7 / Num. unique all: 1617 / % possible all: 98.1

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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: 2.4→37.04 Å / Cor.coef. Fo:Fc: 0.9339 / Cor.coef. Fo:Fc free: 0.8881 / SU R Cruickshank DPI: 0.576 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2374 596 8.05 %RANDOM
Rwork0.1948 ---
all0.1983 11482 --
obs0.1983 11448 97.86 %-
Displacement parametersBiso mean: 42.82 Å2
Baniso -1Baniso -2Baniso -3
1-0.9454 Å20 Å20 Å2
2--1.3374 Å20 Å2
3----2.2828 Å2
Refine analyzeLuzzati coordinate error obs: 0.313 Å
Refinement stepCycle: LAST / Resolution: 2.4→37.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2335 0 24 94 2453
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0072425HARMONIC2
X-RAY DIFFRACTIONt_angle_deg13288HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d835SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes353HARMONIC5
X-RAY DIFFRACTIONt_it2425HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.41
X-RAY DIFFRACTIONt_other_torsion19.94
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2762SEMIHARMONIC4
LS refinement shellResolution: 2.4→2.63 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2526 187 7.18 %
Rwork0.2188 2416 -
all0.2212 2603 -
obs--97.86 %
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)
13.8716-0.63371.14970.7797-0.24044.63840.0312-0.23960.05460.07620.0937-0.12240.02520.0045-0.1248-0.02360.0508-0.0002-0.12070.0317-0.1248-4.5871-16.2749-8.6795
21.1374-0.9690.36622.3333-0.54811.98990.0134-0.2191-0.04940.32770.12170.08980.16710.0819-0.1352-0.0494-0.0358-0.0066-0.09820.0281-0.0826-11.8296-7.212-11.5627
31.95690.515-0.72685.08940.09321.17520.001-0.1880.16310.3091-0.00040.0443-0.10660.0958-0.0006-0.07560.0143-0.0065-0.02190.019-0.0847-10.54467.1988-11.9761
41.8555-0.30160.42071.0437-0.08240.37770.01970.07960.1124-0.0493-0.06910.1009-0.02270.01450.0494-0.05480.00830.0158-0.06310.0128-0.0573-12.965612.7102-24.7836
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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