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

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


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid 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 / Signaling by Erythropoietin ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid 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 / Signaling by Erythropoietin / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / interleukin-12 receptor binding / 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 / post-embryonic hemopoiesis / interleukin-12 receptor complex / activation of Janus kinase activity / interleukin-23 receptor complex / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / positive regulation of platelet activation / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / interleukin-3-mediated signaling pathway / cellular response to interleukin-3 / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / positive regulation of signaling receptor activity / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / Interleukin-20 family signaling / interleukin-6-mediated signaling pathway / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / response to amine / negative regulation of DNA binding / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / cell surface receptor signaling pathway via JAK-STAT / mesoderm development / positive regulation of SMAD protein signal transduction / 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 / Regulation of IFNG signaling / type II interferon-mediated signaling pathway / Erythropoietin activates RAS / Growth hormone receptor signaling / extrinsic apoptotic signaling pathway / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / SH2 domain binding / erythrocyte differentiation / cellular response to dexamethasone stimulus / post-translational protein modification / 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 / positive regulation of apoptotic signaling pathway
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-4HZ / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.78 Å
AuthorsFarmer, L. / Ledeboer, M.W. / Zuccola, H.J.
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)35,3102
Polymers34,8941
Non-polymers4171
Water3,027168
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.012, 102.068, 67.795
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-4HZ / N~2~-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]-N-(2,2,2-trifluoroethyl)-L-alaninamide


Mass: 416.761 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13ClF4N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / 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: 2.33 Å3/Da / Density % sol: 47.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 1.7-2.1 M DL-malic acid pH 7.0, 2mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 8, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.78→48.41 Å / Num. obs: 29880 / % possible obs: 95 % / Redundancy: 5.1 % / Biso Wilson estimate: 24.92 Å2 / Net I/σ(I): 24.7

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
BUSTERphasing
RefinementResolution: 1.78→48.41 Å / Cor.coef. Fo:Fc: 0.9522 / Cor.coef. Fo:Fc free: 0.9395 / SU R Cruickshank DPI: 0.12 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.123 / SU Rfree Blow DPI: 0.114 / SU Rfree Cruickshank DPI: 0.113
RfactorNum. reflection% reflectionSelection details
Rfree0.2132 1510 5.05 %RANDOM
Rwork0.1825 ---
obs0.1841 29880 94.53 %-
Displacement parametersBiso mean: 27.68 Å2
Baniso -1Baniso -2Baniso -3
1-0.8304 Å20 Å20 Å2
2--0.1208 Å20 Å2
3----0.9512 Å2
Refinement stepCycle: 1 / Resolution: 1.78→48.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2360 0 28 168 2556
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0162474HARMONIC1
X-RAY DIFFRACTIONt_angle_deg1.333340HARMONIC1
X-RAY DIFFRACTIONt_dihedral_angle_d897SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes70HARMONIC2
X-RAY DIFFRACTIONt_gen_planes371HARMONIC5
X-RAY DIFFRACTIONt_it2474HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.83
X-RAY DIFFRACTIONt_other_torsion17
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion300SEMIHARMONIC5
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_contact2899SEMIHARMONIC4
LS refinement shellResolution: 1.78→1.84 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2385 149 5.26 %
Rwork0.2047 2686 -
all0.2064 2835 -
obs--94.53 %

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