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- PDB-8b8u: Crystal structure of JAK2 JH2-V617F in complex with HTS-A3 -

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Basic information

Entry
Database: PDB / ID: 8b8u
TitleCrystal structure of JAK2 JH2-V617F in complex with HTS-A3
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Janus kinase / pseudokinase / inhibitor complex / JAK2 / JH2
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 / Signaling by Erythropoietin ...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 / Signaling by Erythropoietin / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / 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 / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of platelet activation / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / acetylcholine receptor binding / 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 / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / 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 / positive regulation of natural killer cell proliferation / mesoderm development / 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 / 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
Chem-T7I / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsHaikarainen, T. / Silvennoinen, O.
Funding support Finland, 1items
OrganizationGrant numberCountry
Academy of Finland Finland
CitationJournal: Pharmaceuticals / Year: 2023
Title: Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain.
Authors: Virtanen, A.T. / Haikarainen, T. / Sampathkumar, P. / Palmroth, M. / Liukkonen, S. / Liu, J. / Nekhotiaeva, N. / Hubbard, S.R. / Silvennoinen, O.
History
DepositionOct 5, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,5099
Polymers66,3382
Non-polymers1,1717
Water7,602422
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7094
Polymers33,1691
Non-polymers5403
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8015
Polymers33,1691
Non-polymers6324
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.276, 56.804, 60.656
Angle α, β, γ (deg.)89.965, 79.144, 71.386
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

#1: Protein Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 33169.004 Da / Num. of mol.: 2 / Mutation: W659A, W777A, F794H, V617F
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-T7I / 3,5-diphenyl-2-(trifluoromethyl)-1~{H}-pyrazolo[1,5-a]pyrimidin-7-one


Mass: 355.313 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H12F3N3O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 422 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.23 Å3/Da / Density % sol: 44.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1M Tris pH 8, 15% PEG4000, 0.2M Na-acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.5→41.19 Å / Num. obs: 87201 / % possible obs: 94.9 % / Redundancy: 3.5 % / Biso Wilson estimate: 18.31 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.039 / Net I/σ(I): 9.2
Reflection shellResolution: 1.5→1.53 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.849 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 3473 / CC1/2: 0.8 / Rpim(I) all: 0.574 / % possible all: 76.2

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
GDAdata collection
xia2data reduction
xia2data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4FVR

4fvr


Resolution: 1.5→41.19 Å / SU ML: 0.2262 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 30.9354
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2594 4317 4.97 %
Rwork0.2224 82589 -
obs0.2243 86906 94.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.98 Å2
Refinement stepCycle: LAST / Resolution: 1.5→41.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4308 0 82 422 4812
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00744551
X-RAY DIFFRACTIONf_angle_d0.88786186
X-RAY DIFFRACTIONf_chiral_restr0.051679
X-RAY DIFFRACTIONf_plane_restr0.0067799
X-RAY DIFFRACTIONf_dihedral_angle_d12.91391673
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.520.354980.35572107X-RAY DIFFRACTION72.27
1.52-1.530.40151290.32652530X-RAY DIFFRACTION86.16
1.53-1.550.38191280.31582633X-RAY DIFFRACTION90.23
1.55-1.570.32591400.29972632X-RAY DIFFRACTION91.21
1.57-1.590.34951420.28282787X-RAY DIFFRACTION93.22
1.59-1.620.30971470.26412662X-RAY DIFFRACTION93.26
1.62-1.640.34041530.26232779X-RAY DIFFRACTION94.92
1.64-1.660.34591670.25742681X-RAY DIFFRACTION93.47
1.66-1.690.33761400.24042742X-RAY DIFFRACTION93.91
1.69-1.720.26431340.22912741X-RAY DIFFRACTION94.48
1.72-1.750.2831360.23422713X-RAY DIFFRACTION94.71
1.75-1.780.28021440.22472842X-RAY DIFFRACTION95.4
1.78-1.810.24631280.22172777X-RAY DIFFRACTION95.56
1.81-1.850.24661340.22722799X-RAY DIFFRACTION95.54
1.85-1.890.27361660.2212764X-RAY DIFFRACTION95.25
1.89-1.930.23711450.21332775X-RAY DIFFRACTION95.55
1.93-1.980.2561460.22612783X-RAY DIFFRACTION96.16
1.98-2.040.26831440.2192798X-RAY DIFFRACTION95.71
2.04-2.10.28881360.21822853X-RAY DIFFRACTION96.05
2.1-2.160.26721250.22742792X-RAY DIFFRACTION96.65
2.16-2.240.26851580.21372817X-RAY DIFFRACTION96.87
2.24-2.330.26061320.20482827X-RAY DIFFRACTION96.76
2.33-2.440.25161590.21492839X-RAY DIFFRACTION97.43
2.44-2.560.26941420.22022831X-RAY DIFFRACTION97.32
2.56-2.730.24981670.21122802X-RAY DIFFRACTION97.41
2.73-2.940.25281540.21892847X-RAY DIFFRACTION97.82
2.94-3.230.26471470.21772847X-RAY DIFFRACTION97.97
3.23-3.70.25651580.20422844X-RAY DIFFRACTION98.46
3.7-4.660.2141690.19792883X-RAY DIFFRACTION98.61
4.66-41.190.24141490.2392862X-RAY DIFFRACTION98.66

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