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- PDB-4rio: Crystal structure of JAK3 kinase domain in complex with a pyrrolo... -

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Basic information

Entry
Database: PDB / ID: 4rio
TitleCrystal structure of JAK3 kinase domain in complex with a pyrrolopyridazine carboxamide inhibitor
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine 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 / tyrosine phosphorylation of STAT protein / negative regulation of T-helper 17 cell lineage commitment / Interleukin-9 signaling ...negative regulation of dendritic cell cytokine 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 / tyrosine phosphorylation of STAT protein / negative regulation of T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / negative regulation of T cell activation / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / growth hormone receptor binding / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / regulation of receptor signaling pathway via JAK-STAT / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / extrinsic component of plasma membrane / Interleukin-20 family signaling / Signaling by ALK / negative regulation of interleukin-10 production / enzyme-linked receptor protein signaling pathway / T cell homeostasis / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / Interleukin-7 signaling / B cell differentiation / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytokine-mediated signaling pathway / 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 / endosome / intracellular signal transduction / 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 / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like 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 / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-3QX / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 Å
AuthorsSack, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.
Authors: Duan, J.J. / Lu, Z. / Jiang, B. / Yang, B.V. / Doweyko, L.M. / Nirschl, D.S. / Haque, L.E. / Lin, S. / Brown, G. / Hynes, J. / Tokarski, J.S. / Sack, J.S. / Khan, J. / Lippy, J.S. / Zhang, R. ...Authors: Duan, J.J. / Lu, Z. / Jiang, B. / Yang, B.V. / Doweyko, L.M. / Nirschl, D.S. / Haque, L.E. / Lin, S. / Brown, G. / Hynes, J. / Tokarski, J.S. / Sack, J.S. / Khan, J. / Lippy, J.S. / Zhang, R.F. / Pitt, S. / Shen, G. / Pitts, W.J. / Carter, P.H. / Barrish, J.C. / Nadler, S.G. / Salter-Cid, L.M. / McKinnon, M. / Fura, A. / Schieven, G.L. / Wrobleski, S.T.
History
DepositionOct 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5302
Polymers33,2541
Non-polymers2761
Water39622
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.540, 75.440, 87.980
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-3QX / 4-{[(1R,2S)-2-fluoro-2-methylcyclopentyl]amino}pyrrolo[1,2-b]pyridazine-3-carboxamide


Mass: 276.309 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H17FN4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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% PEG-3350, 200MM MAGNESIUM CHLORIDE 100MM BIS-TRIS PH 5.8, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Apr 2, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 9255 / % possible obs: 99.6 % / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 64.08 Å2 / Rmerge(I) obs: 0.179 / Net I/σ(I): 9.9
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.611 / Mean I/σ(I) obs: 2.7 / % possible all: 98.9

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.69→41.83 Å / Cor.coef. Fo:Fc: 0.8916 / Cor.coef. Fo:Fc free: 0.8595 / SU R Cruickshank DPI: 1.905 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2814 464 5.04 %RANDOM
Rwork0.2148 ---
obs0.2181 9202 99.65 %-
Displacement parametersBiso mean: 55.28 Å2
Baniso -1Baniso -2Baniso -3
1--17.3303 Å20 Å20 Å2
2--21.0098 Å20 Å2
3----3.6796 Å2
Refine analyzeLuzzati coordinate error obs: 0.338 Å
Refinement stepCycle: LAST / Resolution: 2.69→41.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2206 0 20 22 2248
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012281HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.133100HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d769SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes50HARMONIC2
X-RAY DIFFRACTIONt_gen_planes349HARMONIC5
X-RAY DIFFRACTIONt_it2281HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion19.71
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion282SEMIHARMONIC5
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_contact2625SEMIHARMONIC4
LS refinement shellResolution: 2.69→3.01 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.3143 135 5.33 %
Rwork0.2152 2398 -
all0.2205 2533 -
obs--99.65 %

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