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- PDB-6d2i: JAK2 Pseudokinase V617F in complex with AT9283 -

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Basic information

Entry
Database: PDB / ID: 6d2i
TitleJAK2 Pseudokinase V617F in complex with AT9283
ComponentsTyrosine-protein kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE / PSEUDOKINASE DOMAIN / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of alpha-beta T cell activation / positive regulation of cell activation / defense response to symbiont / 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 ...regulation of alpha-beta T cell activation / positive regulation of cell activation / defense response to symbiont / 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 / regulation of cell-cell adhesion / positive regulation of interleukin-17 production / positive regulation of natural killer cell proliferation / response to tumor necrosis factor / positive regulation of intracellular signal transduction / 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 / immune system process / 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
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-35R / Tyrosine-protein kinase JAK2 / Tyrosine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.192 Å
AuthorsLi, Q. / Li, K. / Eck, M.J.
CitationJournal: ACS Chem. Biol. / Year: 2019
Title: Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain.
Authors: McNally, R. / Li, Q. / Li, K. / Dekker, C. / Vangrevelinghe, E. / Jones, M. / Chene, P. / Machauer, R. / Radimerski, T. / Eck, M.J.
History
DepositionApr 13, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2019Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase
B: Tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3014
Polymers62,5382
Non-polymers7632
Water00
1
A: Tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6502
Polymers31,2691
Non-polymers3811
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6502
Polymers31,2691
Non-polymers3811
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.905, 91.131, 113.100
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


Mass: 31268.936 Da / Num. of mol.: 2 / Mutation: W659A, W777A, F794H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q506Q0, UniProt: O60674*PLUS, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-35R / 1-cyclopropyl-3-{3-[5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea


Mass: 381.432 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23N7O2
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: 2.64 Å3/Da / Density % sol: 53.36 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1M Tris pH 8, 0.1M MgAcetate and 24% w/v PEG4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 0.984 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 3, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.984 Å / Relative weight: 1
ReflectionResolution: 3.19→42.35 Å / Num. obs: 11293 / % possible obs: 98.2 % / Redundancy: 5.6 % / Biso Wilson estimate: 22.27 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.138 / Rpim(I) all: 0.092 / Rrim(I) all: 0.167 / Net I/σ(I): 8.9
Reflection shellResolution: 3.19→3.41 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.7115 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1904 / CC1/2: 0.774 / Rpim(I) all: 0.473 / Rrim(I) all: 0.86 / % possible all: 93.7

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L00

4l00


Resolution: 3.192→42.264 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2896 572 5.09 %
Rwork0.2709 --
obs0.2718 11238 97.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.192→42.264 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4389 0 56 0 4445
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024553
X-RAY DIFFRACTIONf_angle_d0.5066158
X-RAY DIFFRACTIONf_dihedral_angle_d15.0152750
X-RAY DIFFRACTIONf_chiral_restr0.039670
X-RAY DIFFRACTIONf_plane_restr0.003791
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1919-3.5130.30861250.31182563X-RAY DIFFRACTION96
3.513-4.0210.26121520.27762643X-RAY DIFFRACTION99
4.021-5.06470.291330.24322694X-RAY DIFFRACTION99
5.0647-42.26810.29971620.27682766X-RAY DIFFRACTION98

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