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- PDB-4ytc: Discovery of VX-509 (Decernotinib): A Potent and Selective Janus ... -

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Entry
Database: PDB / ID: 4ytc
TitleDiscovery of VX-509 (Decernotinib): A Potent and Selective Janus kinase (JAK) 3 Inhibitor for the Treatment of Autoimmune Disease
ComponentsTyrosine-protein kinase JAK2
KeywordsTransferase/Transferase Inhibitor / janus kinase / kinase / inhibitor / autoimmune / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / interleukin-12 receptor binding / post-embryonic hemopoiesis / collagen-activated signaling pathway / Erythropoietin activates STAT5 / Erythropoietin activates Phospholipase C gamma (PLCG) / interleukin-5-mediated signaling pathway / response to interleukin-12 / positive regulation of leukocyte proliferation / activation of Janus kinase activity / interleukin-12 receptor complex / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / positive regulation of platelet activation / positive regulation of MHC class II biosynthetic process / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / acetylcholine receptor binding / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / Signaling by Leptin / positive regulation of signaling receptor activity / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / positive regulation of cell-substrate adhesion / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / positive regulation of epithelial cell apoptotic process / axon regeneration / peptide hormone receptor binding / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / Interleukin-20 family signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / Prolactin receptor signaling / positive regulation of interleukin-17 production / negative regulation of DNA binding / MAPK3 (ERK1) activation / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / mesoderm development / positive regulation of natural killer cell proliferation / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / positive regulation of apoptotic signaling pathway / extrinsic apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / extrinsic component of cytoplasmic side of plasma membrane / SH2 domain binding / cellular response to dexamethasone stimulus / post-translational protein modification / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / caveola / endosome lumen / positive regulation of cell differentiation
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / 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 ...Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / 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 central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / SH2 domain / Src homology 2 (SH2) domain profile. / 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-4HW / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.16 Å
AuthorsZuccola, H.J. / Ledeboer, M.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.
Authors: Farmer, L.J. / Ledeboer, M.W. / Hoock, T. / Arnost, M.J. / Bethiel, R.S. / Bennani, Y.L. / Black, J.J. / Brummel, C.L. / Chakilam, A. / Dorsch, W.A. / Fan, B. / Cochran, J.E. / Halas, S. / ...Authors: Farmer, L.J. / Ledeboer, M.W. / Hoock, T. / Arnost, M.J. / Bethiel, R.S. / Bennani, Y.L. / Black, J.J. / Brummel, C.L. / Chakilam, A. / Dorsch, W.A. / Fan, B. / Cochran, J.E. / Halas, S. / Harrington, E.M. / Hogan, J.K. / Howe, D. / Huang, H. / Jacobs, D.H. / Laitinen, L.M. / Liao, S. / Mahajan, S. / Marone, V. / Martinez-Botella, G. / McCarthy, P. / Messersmith, D. / Namchuk, M. / Oh, L. / Penney, M.S. / Pierce, A.C. / Raybuck, S.A. / Rugg, A. / Salituro, F.G. / Saxena, K. / Shannon, D. / Shlyakter, D. / Swenson, L. / Tian, S.K. / Town, C. / Wang, J. / Wang, T. / Wannamaker, M.W. / Winquist, R.J. / Zuccola, H.J.
History
DepositionMar 17, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2015Group: Other
Revision 1.2Sep 23, 2015Group: Database references
Revision 1.3Oct 7, 2015Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2382
Polymers34,8941
Non-polymers3441
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.569, 101.516, 68.377
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 34893.723 Da / Num. of mol.: 1 / Fragment: UNP residues 842-1132
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-4HW / N~3~-phenyl-1-[6-(phenylamino)pyrimidin-4-yl]-1H-1,2,4-triazole-3,5-diamine


Mass: 344.373 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16N8
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 91 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.35 Å3/Da / Density % sol: 47.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 1.7-2.1M dl-malic acid, pH 7.0, 2mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.16→40.76 Å / Num. obs: 17889 / % possible obs: 100 % / Redundancy: 4.8 % / Biso Wilson estimate: 34.07 Å2 / Net I/σ(I): 15.1

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
BUSTERphasing
RefinementResolution: 2.16→40.76 Å / Cor.coef. Fo:Fc: 0.9389 / Cor.coef. Fo:Fc free: 0.929 / SU R Cruickshank DPI: 0.232 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.235 / SU Rfree Blow DPI: 0.171 / SU Rfree Cruickshank DPI: 0.172
RfactorNum. reflection% reflectionSelection details
Rfree0.2128 913 5.1 %RANDOM
Rwork0.1898 ---
obs0.191 17889 99.34 %-
Displacement parametersBiso mean: 36.24 Å2
Baniso -1Baniso -2Baniso -3
1-3.2908 Å20 Å20 Å2
2---1.7922 Å20 Å2
3----1.4986 Å2
Refinement stepCycle: 1 / Resolution: 2.16→40.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2378 0 26 91 2495
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0152490HARMONIC1
X-RAY DIFFRACTIONt_angle_deg1.453376HARMONIC1
X-RAY DIFFRACTIONt_dihedral_angle_d896SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes70HARMONIC2
X-RAY DIFFRACTIONt_gen_planes379HARMONIC5
X-RAY DIFFRACTIONt_it2490HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.67
X-RAY DIFFRACTIONt_other_torsion17.33
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion298SEMIHARMONIC5
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_contact2702SEMIHARMONIC4
LS refinement shellResolution: 2.16→2.29 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2325 118 4.32 %
Rwork0.1946 2616 -
all0.1963 2734 -
obs--99.34 %

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