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- PDB-4hvd: JAK3 kinase domain in complex with 2-Cyclopropyl-5H-pyrrolo[2,3-b... -

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Basic information

Entry
Database: PDB / ID: 4hvd
TitleJAK3 kinase domain in complex with 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide
ComponentsTyrosine-protein kinase JAK3
KeywordsTransferase/Transferase Inhibitor / Kinase-Inhibitor Complex / 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 cell activation / Interleukin-9 signaling / Interleukin-21 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 cell activation / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / tyrosine phosphorylation of STAT protein / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / Interleukin-2 signaling / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / Signaling by ALK / extrinsic component of plasma membrane / negative regulation of interleukin-10 production / Interleukin-20 family signaling / enzyme-linked receptor protein signaling pathway / T cell homeostasis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / extrinsic component of cytoplasmic side of plasma membrane / 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 / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / regulation of apoptotic process / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / adaptive immune response / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / 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 / FERM domain / FERM domain profile. ...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 / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-933 / 1-phenylurea / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 Å
AuthorsKuglstatter, A. / Shao, A.
CitationJournal: J.Med.Chem. / Year: 2013
Title: 3-Amido Pyrrolopyrazine JAK Kinase Inhibitors: Development of a JAK3 vs JAK1 Selective Inhibitor and Evaluation in Cellular and in Vivo Models.
Authors: Soth, M. / Hermann, J.C. / Yee, C. / Alam, M. / Barnett, J.W. / Berry, P. / Browner, M.F. / Frank, K. / Frauchiger, S. / Harris, S. / He, Y. / Hekmat-Nejad, M. / Hendricks, T. / Henningsen, ...Authors: Soth, M. / Hermann, J.C. / Yee, C. / Alam, M. / Barnett, J.W. / Berry, P. / Browner, M.F. / Frank, K. / Frauchiger, S. / Harris, S. / He, Y. / Hekmat-Nejad, M. / Hendricks, T. / Henningsen, R. / Hilgenkamp, R. / Ho, H. / Hoffman, A. / Hsu, P.Y. / Hu, D.Q. / Itano, A. / Jaime-Figueroa, S. / Jahangir, A. / Jin, S. / Kuglstatter, A. / Kutach, A.K. / Liao, C. / Lynch, S. / Menke, J. / Niu, L. / Patel, V. / Railkar, A. / Roy, D. / Shao, A. / Shaw, D. / Steiner, S. / Sun, Y. / Tan, S.L. / Wang, S. / Vu, M.D.
History
DepositionNov 6, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 30, 2013Group: Database references
Revision 1.2Sep 20, 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0363
Polymers35,6141
Non-polymers4232
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.816, 75.416, 89.392
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: 35613.598 Da / Num. of mol.: 1 / Fragment: RESIDUES 811-1124 / Mutation: 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-PHU / 1-phenylurea / Phenylurea


Mass: 136.151 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8N2O
#3: Chemical ChemComp-933 / 2-cyclopropyl-N-[(2S)-3,3-dimethylbutan-2-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide


Mass: 286.372 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H22N4O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 131 / 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: 2.22 Å3/Da / Density % sol: 44.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 30% PEG3350, 0.1M MES, 0.2M MgCl, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97929 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 1.85→44.68 Å / Num. obs: 21755 / % possible obs: 82.73 % / Redundancy: 4.7 % / Biso Wilson estimate: 26.6 Å2 / Rsym value: 0.05 / Net I/σ(I): 26.9
Reflection shellResolution: 1.85→1.9 Å / Redundancy: 1.5 % / Mean I/σ(I) obs: 2.3 / Num. unique all: 340 / Rsym value: 0.263 / % possible all: 17

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 1YVJ

1yvj


Resolution: 1.85→34.74 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.926 / SU B: 10.022 / SU ML: 0.13 / Cross valid method: THROUGHOUT / ESU R: 0.197 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25918 1167 5.1 %RANDOM
Rwork0.22285 ---
obs0.22466 21755 82.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 35.014 Å2
Baniso -1Baniso -2Baniso -3
1-1.46 Å20 Å20 Å2
2---0.25 Å20 Å2
3----1.21 Å2
Refinement stepCycle: LAST / Resolution: 1.85→34.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2215 0 31 131 2377
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222304
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.9761.9973119
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7515273
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.89422.804107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.54415392
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.651521
X-RAY DIFFRACTIONr_chiral_restr0.0670.2330
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021777
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1780.2992
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3040.21563
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1230.2147
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1520.232
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1120.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5611.51429
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.99222219
X-RAY DIFFRACTIONr_scbond_it1.2331007
X-RAY DIFFRACTIONr_scangle_it2.0284.5897
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.277 16 -
Rwork0.297 323 -
obs--17.04 %
Refinement TLS params.Method: refined / Origin x: 3.2617 Å / Origin y: -13.616 Å / Origin z: -14.7465 Å
111213212223313233
T-0.0173 Å20.0155 Å20.0074 Å2--0.0388 Å20.022 Å2---0.0048 Å2
L0.3565 °2-0.0566 °2-0.1474 °2-0.3347 °20.3679 °2--0.9277 °2
S0.0337 Å °0.0154 Å °0.0353 Å °-0.0598 Å °-0.0307 Å °-0.0137 Å °0.0008 Å °0.0178 Å °-0.003 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1301 - 1431
2X-RAY DIFFRACTION1A1201 - 1202
3X-RAY DIFFRACTION1A815 - 1101

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