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- PDB-3io7: 2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibit... -

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Basic information

Entry
Database: PDB / ID: 3io7
Title2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2
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 / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / 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 / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / 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 / collagen-activated signaling pathway / interleukin-23-mediated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / response to interleukin-12 / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / positive regulation of platelet activation / interleukin-3-mediated signaling pathway / cellular response to interleukin-3 / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of signaling receptor activity / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / growth hormone receptor signaling pathway / axon regeneration / response to hydroperoxide / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / peptide hormone receptor binding / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / response to amine / negative regulation of DNA binding / extrinsic component of cytoplasmic side of plasma membrane / mesoderm development / positive regulation of nitric-oxide synthase biosynthetic process / positive regulation of interleukin-17 production / MAPK1 (ERK2) activation / 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 / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / Growth hormone receptor signaling / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / post-translational protein modification / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / 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 / SH2 domain / 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 ...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 / SH2 domain / 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 / 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-1P5 / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.6 Å
AuthorsZuccola, H.J. / Ledeboer, M.W. / Pierce, A.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: 2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.
Authors: Ledeboer, M.W. / Pierce, A.C. / Duffy, J.P. / Gao, H. / Messersmith, D. / Salituro, F.G. / Nanthakumar, S. / Come, J. / Zuccola, H.J. / Swenson, L. / Shlyakter, D. / Mahajan, S. / Hoock, T. ...Authors: Ledeboer, M.W. / Pierce, A.C. / Duffy, J.P. / Gao, H. / Messersmith, D. / Salituro, F.G. / Nanthakumar, S. / Come, J. / Zuccola, H.J. / Swenson, L. / Shlyakter, D. / Mahajan, S. / Hoock, T. / Fan, B. / Tsai, W.J. / Kolaczkowski, E. / Carrier, S. / Hogan, J.K. / Zessis, R. / Pazhanisamy, S. / Bennani, Y.L.
History
DepositionAug 13, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Mar 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_src_syn / struct_conn / 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 / _entity.details / _struct_conn.pdbx_leaving_atom_flag / _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 JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,1772
Polymers36,7831
Non-polymers3941
Water64936
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.922, 101.752, 67.194
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Detailsbiological unit is the same as asym.

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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: Jak kinase domain(UNP residue 842-1132)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Plasmid: pBEV1 / Production host: Baculovirus / Strain (production host): Sf9
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-1P5 / (3S)-1-[6-(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-4-yl]-N,N-diethylpiperidine-3-carboxamide


Mass: 394.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H26N8O / Details: chemical synthesis
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 2.34 Å3/Da / Density % sol: 47.54 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: 2.1 - 1.5 D-L malic acid, pH no buffer added, VAPOR DIFFUSION, temperature 298K
PH range: no buffer added

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 1, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→100 Å / Num. all: 10222 / Num. obs: 9424 / % possible obs: 92.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Biso Wilson estimate: 37.6 Å2 / Rmerge(I) obs: 0.088 / Χ2: 0.78 / Net I/σ(I): 7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.6-2.693.20.3167960.68579.4
2.69-2.83.70.3078480.71786.1
2.8-2.933.80.2719500.7593.6
2.93-3.083.80.2089480.76495.7
3.08-3.283.80.1459850.78796.3
3.28-3.533.80.0979610.82595.8
3.53-3.883.80.0689790.82495
3.88-4.453.80.059760.83194.8
4.45-5.63.80.0469710.79793.8
5.6-1003.60.03810100.77391.4

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
BOSdata collection
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.6→20 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.849 / WRfactor Rfree: 0.253 / WRfactor Rwork: 0.177 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.784 / SU B: 12.843 / SU ML: 0.281 / SU Rfree: 0.427 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.427 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.294 710 7.6 %RANDOM
Rwork0.199 ---
all0.206 ---
obs0.206 9384 91.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 58.37 Å2 / Biso mean: 28.757 Å2 / Biso min: 2.07 Å2
Baniso -1Baniso -2Baniso -3
1--2.2 Å20 Å20 Å2
2--2.4 Å20 Å2
3----0.21 Å2
Refinement stepCycle: LAST / Resolution: 2.6→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2362 0 29 36 2427
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222444
X-RAY DIFFRACTIONr_angle_refined_deg1.3261.9883293
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0345281
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.74124.113124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.66315459
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7811518
X-RAY DIFFRACTIONr_chiral_restr0.090.2343
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021857
X-RAY DIFFRACTIONr_nbd_refined0.2010.21011
X-RAY DIFFRACTIONr_nbtor_refined0.3080.21619
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.150.268
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1520.245
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1460.25
X-RAY DIFFRACTIONr_mcbond_it0.6261.51462
X-RAY DIFFRACTIONr_mcangle_it1.12622292
X-RAY DIFFRACTIONr_scbond_it1.30631122
X-RAY DIFFRACTIONr_scangle_it2.1264.51001
LS refinement shellResolution: 2.596→2.662 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.32 41 -
Rwork0.249 481 -
all-522 -
obs--71.6 %

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