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- PDB-9nd5: JAK2 pseudokinase domain in complex with diaminotriazole covalent... -

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Basic information

Entry
Database: PDB / ID: 9nd5
TitleJAK2 pseudokinase domain in complex with diaminotriazole covalent inhibitor
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / JAK2 kinase / Pseudokinase domain / Allosteric inhibitors / Pseudokinase domain inhibitors / Covalent inhibitors / TRANSFERASE / 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 / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / thrombopoietin-mediated signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / type 1 angiotensin receptor binding / post-embryonic hemopoiesis / interleukin-12 receptor complex / erythropoietin-mediated signaling pathway / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of MHC class II biosynthetic process / positive regulation of NK T cell proliferation / acetylcholine receptor binding / positive regulation of platelet activation / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / Interleukin-12 signaling / positive regulation of epithelial cell apoptotic process / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / regulation of nitric oxide biosynthetic process / growth hormone receptor binding / positive regulation of cell-substrate adhesion / axon regeneration / extrinsic component of cytoplasmic side of plasma membrane / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / negative regulation of cardiac muscle cell apoptotic process / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of tyrosine phosphorylation of STAT protein / negative regulation of cell-cell adhesion / extrinsic component of plasma membrane / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / peptide hormone receptor binding / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / MAPK3 (ERK1) activation / response to amine / Prolactin receptor signaling / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / mesoderm development / positive regulation of interleukin-17 production / positive regulation of natural killer cell proliferation / response to tumor necrosis factor / signaling receptor activator activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / positive regulation of SMAD protein signal transduction / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / cellular response to dexamethasone stimulus / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Growth hormone receptor signaling / phosphatidylinositol 3-kinase binding / Erythropoietin activates RAS / positive regulation of vascular associated smooth muscle cell proliferation / Signaling by CSF3 (G-CSF) / extrinsic apoptotic signaling pathway / actin filament polymerization / positive regulation of T cell proliferation / negative regulation of cytokine production involved in inflammatory response / SH2 domain binding / post-translational protein modification / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / endosome lumen / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / erythrocyte differentiation / tumor necrosis factor-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity
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 / : ...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 / SH2 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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsPrimi, M.C. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R35CA242461-06 United States
CitationJournal: To Be Published
Title: JAK2 pseudokinase domain in complex with diaminotriazole covalent inhibitor
Authors: Primi, M.C. / Eck, M.J.
History
DepositionFeb 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release

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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)32,8862
Polymers32,4271
Non-polymers4581
Water1,78399
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.165, 61.037, 86.154
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 JAK2 / Janus kinase 2 / JAK-2


Mass: 32427.193 Da / Num. of mol.: 1
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-A1BXA / 4-{[5-amino-1-(3-{[fluorodi(hydroxy)-lambda~4~-sulfanyl]oxy}benzoyl)-1H-1,2,4-triazol-3-yl]amino}benzene-1-sulfonamide


Mass: 458.445 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H15FN6O6S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.32 Å3/Da / Density % sol: 46.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 200 mM Sodium Acetate, 100 mM Tris-HCl, 20% polyethylene glycol 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 10, 2023
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.4→49.8 Å / Num. obs: 11879 / % possible obs: 96.7 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 9.9
Reflection shellResolution: 2.4→2.49 Å / Rmerge(I) obs: 0.361 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 11879

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Processing

Software
NameVersionClassification
PHENIX(1.21.2_5419: ???)refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→49.8 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 29.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2778 634 5.34 %
Rwork0.2107 --
obs0.2142 11879 96.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→49.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2191 0 29 99 2319
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007
X-RAY DIFFRACTIONf_angle_d0.919
X-RAY DIFFRACTIONf_dihedral_angle_d17.017873
X-RAY DIFFRACTIONf_chiral_restr0.053337
X-RAY DIFFRACTIONf_plane_restr0.008398
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.590.3411390.29022227X-RAY DIFFRACTION99
2.59-2.850.30971300.27222217X-RAY DIFFRACTION97
2.85-3.260.33461420.2512249X-RAY DIFFRACTION99
3.26-4.10.28411130.19652225X-RAY DIFFRACTION95
4.1-49.80.21041100.17142327X-RAY DIFFRACTION95

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