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- PDB-6ny4: Crystal structure of JAK3 kinase domain in complex with a pyrrolo... -

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Basic information

Entry
Database: PDB / ID: 6ny4
TitleCrystal structure of JAK3 kinase domain in complex with a pyrrolopyridazine carboxamide inhibitor
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine production / negative regulation of FasL production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / negative regulation of T-helper 17 cell lineage commitment / interleukin-7-mediated signaling pathway / Interleukin-9 signaling ...negative regulation of dendritic cell cytokine production / negative regulation of FasL production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / negative regulation of T-helper 17 cell lineage commitment / interleukin-7-mediated signaling pathway / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / negative regulation of T cell activation / regulation of T cell apoptotic process / interleukin-2-mediated signaling pathway / negative regulation of interleukin-12 production / tyrosine phosphorylation of STAT protein / interleukin-15-mediated signaling pathway / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / Interleukin-2 signaling / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / extrinsic component of plasma membrane / Signaling by ALK / Interleukin-20 family signaling / negative regulation of interleukin-10 production / enzyme-linked receptor protein signaling pathway / extrinsic component of cytoplasmic side of plasma membrane / T cell homeostasis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / Interleukin-7 signaling / B cell differentiation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / cytoplasmic side of plasma membrane / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / adaptive immune response / Potential therapeutics for SARS / cell differentiation / cytoskeleton / intracellular signal transduction / endosome / protein phosphorylation / innate immune response / ATP binding / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak3 / 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 Jak3 / 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 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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-Z3A / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.33 Å
AuthorsSack, J.S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis.
Authors: Spergel, S.H. / Mertzman, M.E. / Kempson, J. / Guo, J. / Stachura, S. / Haque, L. / Lippy, J.S. / Zhang, R.F. / Galella, M. / Pitt, S. / Shen, G. / Fura, A. / Gillooly, K. / McIntyre, K.W. / ...Authors: Spergel, S.H. / Mertzman, M.E. / Kempson, J. / Guo, J. / Stachura, S. / Haque, L. / Lippy, J.S. / Zhang, R.F. / Galella, M. / Pitt, S. / Shen, G. / Fura, A. / Gillooly, K. / McIntyre, K.W. / Tang, V. / Tokarski, J. / Sack, J.S. / Khan, J. / Carter, P.H. / Barrish, J.C. / Nadler, S.G. / Salter-Cid, L.M. / Schieven, G.L. / Wrobleski, S.T. / Pitts, W.J.
History
DepositionFeb 11, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_radiation_wavelength.wavelength

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5942
Polymers33,2541
Non-polymers3401
Water88349
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.950, 75.530, 87.790
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 Tyrosine-protein kinase JAK3 / Janus kinase 3 / JAK-3 / Leukocyte janus kinase / L-JAK


Mass: 33254.016 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 810-1100) / Mutation: C811S,C1040S,C1048S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-Z3A / 4-{[(2R,3R)-1,3-dihydroxybutan-2-yl]amino}-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide


Mass: 340.376 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20N4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / 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: 2.37 Å3/Da / Density % sol: 48.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.8
Details: 30% PEG3350, 200 mM magnesium chloride, 100 mM Bis-Tris, pH 5.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Sep 15, 2011
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.12→87.75 Å / Num. obs: 17298 / % possible obs: 94.6 % / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 54.95 Å2 / Rmerge(I) obs: 0.051 / Net I/σ(I): 19.7
Reflection shellResolution: 2.12→2.23 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.579 / Mean I/σ(I) obs: 2.4 / % possible all: 96.4

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
RefinementResolution: 2.33→37.95 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.919 / SU R Cruickshank DPI: 0.328 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.34 / SU Rfree Blow DPI: 0.223 / SU Rfree Cruickshank DPI: 0.223
RfactorNum. reflection% reflectionSelection details
Rfree0.241 686 4.95 %RANDOM
Rwork0.215 ---
obs0.216 13857 99.2 %-
Displacement parametersBiso mean: 56.28 Å2
Baniso -1Baniso -2Baniso -3
1--13.3694 Å20 Å20 Å2
2--9.9106 Å20 Å2
3---3.4588 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2.33→37.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2115 0 25 49 2189
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012192HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.062981HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d722SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes391HARMONIC5
X-RAY DIFFRACTIONt_it2192HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.98
X-RAY DIFFRACTIONt_other_torsion16.55
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion275SEMIHARMONIC5
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_contact2532SEMIHARMONIC4
LS refinement shellResolution: 2.33→2.35 Å / Total num. of bins used: 34
RfactorNum. reflection% reflection
Rfree0.3198 -4.9 %
Rwork0.2319 388 -
all0.2363 408 -
obs--81.76 %

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