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- PDB-6nzp: CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN)... -

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Basic information

Entry
Database: PDB / ID: 6nzp
TitleCRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH COMPOUND-11 AKA 6-CYCLOPROPANEAMIDO-4-{[2-METHOXY-3-(1-METHYL-1H-1,2,4-TRI AZOL-3-YL)PHENYL]AMINO}-N-(?H?)METHYLPYRIDAZINE-3-CARBOXAMIDE
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / JTK1 / Pseudo Kinase
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-LB7 / Hydrogenase-2 large chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsKhan, J.A.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.
Authors: Wrobleski, S.T. / Moslin, R. / Lin, S. / Zhang, Y. / Spergel, S. / Kempson, J. / Tokarski, J.S. / Strnad, J. / Zupa-Fernandez, A. / Cheng, L. / Shuster, D. / Gillooly, K. / Yang, X. / ...Authors: Wrobleski, S.T. / Moslin, R. / Lin, S. / Zhang, Y. / Spergel, S. / Kempson, J. / Tokarski, J.S. / Strnad, J. / Zupa-Fernandez, A. / Cheng, L. / Shuster, D. / Gillooly, K. / Yang, X. / Heimrich, E. / McIntyre, K.W. / Chaudhry, C. / Khan, J. / Ruzanov, M. / Tredup, J. / Mulligan, D. / Xie, D. / Sun, H. / Huang, C. / D'Arienzo, C. / Aranibar, N. / Chiney, M. / Chimalakonda, A. / Pitts, W.J. / Lombardo, L. / Carter, P.H. / Burke, J.R. / Weinstein, D.S.
History
DepositionFeb 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 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
B: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,8795
Polymers70,9982
Non-polymers8803
Water1,36976
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1050 Å2
ΔGint-8 kcal/mol
Surface area22690 Å2
2
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9222
Polymers35,4991
Non-polymers4221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9573
Polymers35,4991
Non-polymers4582
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.630, 66.970, 75.100
Angle α, β, γ (deg.)90.00, 113.34, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 35499.156 Da / Num. of mol.: 2 / Fragment: Pseudo kinase domain, residues 575-869
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-LB7 / 6-[(cyclopropanecarbonyl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-N-methylpyridazine-3-carboxamide


Mass: 422.440 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H22N8O3
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 2.33 Å3/Da / Density % sol: 47.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 200 mM ammonium sulfate, and 100 mM Cacodylate buffer, pH 7.5, 30%(W/V) PEG 5000 (Methyl Ether)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 16, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.34→48.04 Å / Num. obs: 16712 / % possible obs: 89.6 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 53.65 Å2 / Rmerge(I) obs: 0.093 / Rsym value: 0.06 / Net I/σ(I): 9.5
Reflection shellResolution: 2.34→2.61 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.865 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 16712 / Rsym value: 0 / % possible all: 62.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WOV

4wov


Resolution: 2.35→48.04 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.902 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.687 / SU Rfree Blow DPI: 0.32
RfactorNum. reflection% reflectionSelection details
Rfree0.238 783 4.69 %RANDOM
Rwork0.189 ---
obs0.191 16711 60.9 %-
Displacement parametersBiso mean: 47.74 Å2
Baniso -1Baniso -2Baniso -3
1-2.1885 Å20 Å20.8498 Å2
2---0.5836 Å20 Å2
3----1.6049 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 2.35→48.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4020 0 63 76 4159
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014233HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.145791HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1427SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes764HARMONIC5
X-RAY DIFFRACTIONt_it4233HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.98
X-RAY DIFFRACTIONt_other_torsion20.1
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion530SEMIHARMONIC5
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_contact4911SEMIHARMONIC4
LS refinement shellResolution: 2.35→2.53 Å / Total num. of bins used: 39
RfactorNum. reflection% reflection
Rfree0.2675 -4.43 %
Rwork0.2319 410 -
all0.2336 429 -
obs--7.91 %

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