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- PDB-3kck: A Novel Chemotype of Kinase Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3kck
TitleA Novel Chemotype of Kinase Inhibitors
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / kinase / inhibitor / jak2 / janus kinase / ATP-binding / Chromosomal rearrangement / Disease mutation / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Proto-oncogene / SH2 domain / Tyrosine-protein kinase
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-3KC / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsZuccola, H.J. / Wang, T. / Ledeboer, M.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: A novel chemotype of kinase inhibitors: Discovery of 3,4-ring fused 7-azaindoles and deazapurines as potent JAK2 inhibitors.
Authors: Wang, T. / Ledeboer, M.W. / Duffy, J.P. / Pierce, A.C. / Zuccola, H.J. / Block, E. / Shlyakter, D. / Hogan, J.K. / Bennani, Y.L.
History
DepositionOct 21, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,1292
Polymers36,7831
Non-polymers3461
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)95.156, 100.803, 67.621
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 36782.809 Da / Num. of mol.: 1 / Fragment: jak2 kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Plasmid: pBEV1 / Cell line (production host): Sf9 insect cells / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-3KC / 3-chloro-4-(4H-3,4,7-triazadibenzo[cd,f]azulen-6-yl)phenol


Mass: 345.782 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H12ClN3O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 2.2 Å3/Da / Density % sol: 44.2 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7
Details: 2.1 - 1.5 D-L malic acid, pH 7, vapor diffusion, temperature 298K

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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 315 / Detector: CCD / Date: Jun 29, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionRedundancy: 4.81 % / Number: 80749 / Rmerge(I) obs: 0.091 / Χ2: 0.95 / D res high: 2.2 Å / D res low: 40.41 Å / Num. obs: 16675 / % possible obs: 98.9
Diffraction reflection shell

ID: 1

Highest resolution (Å)Lowest resolution (Å)% possible obs (%)Rmerge(I) obsChi squaredRedundancyRejects
4.7440.4195.80.0520.674.845
3.764.7497.40.0520.74.750
3.293.7698.50.0770.74.71158
2.993.29990.1250.884.77134
2.772.9999.30.1720.924.8103
2.612.7799.60.2111.084.8439
2.482.6199.80.2671.14.8630
2.372.4899.90.3071.134.8633
2.282.371000.3371.124.856
2.22.2899.90.3631.134.868
ReflectionResolution: 2.2→40.41 Å / Num. all: 16862 / Num. obs: 16675 / % possible obs: 98.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.81 % / Biso Wilson estimate: 32.1 Å2 / Rmerge(I) obs: 0.091 / Rsym value: 0.101 / Χ2: 0.95 / Net I/σ(I): 7.9 / Scaling rejects: 606
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible all
2.2-2.284.860.3632.6794516321.1399.9
2.28-2.374.850.3372.7815216781.12100
2.37-2.484.860.3073.1817316761.1399.9
2.48-2.614.860.2673.6799516381.199.8
2.61-2.774.840.2114.3813616721.0899.6
2.77-2.994.80.1725.7805516570.9299.3
2.99-3.294.770.1257.6807516650.8899
3.29-3.764.710.07711.9805916760.798.5
3.76-4.744.70.05218785016610.797.4
4.74-40.414.80.05219.6830917200.6795.8

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Processing

Software
NameVersionClassificationNB
d*TREK9.9.3Ddata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
BOSdata collection
d*TREKdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.2→20 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.877 / WRfactor Rfree: 0 / WRfactor Rwork: 0 / FOM work R set: 0.743 / SU ML: 0.192 / SU R Cruickshank DPI: 0.352 / SU Rfree: 0.271 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.352 / ESU R Free: 0.271 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.296 1291 7.8 %RANDOM
Rwork0.225 ---
all0.244 16862 --
obs0.244 16648 98.9 %-
Displacement parametersBiso mean: 29.498 Å2
Baniso -1Baniso -2Baniso -3
1--0.9 Å20 Å20 Å2
2--0.94 Å20 Å2
3----0.04 Å2
Refinement stepCycle: LAST / Resolution: 2.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2383 0 25 98 2506

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