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- PDB-6g3c: Crystal Structure of JAK2-V617F pseudokinase domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 6g3c
TitleCrystal Structure of JAK2-V617F pseudokinase domain in complex with Compound 2
ComponentsTyrosine-protein kinase
KeywordsTRANSFERASE / JANUS PROTEIN KINASE / PSEUDOKINASE / PHOSPHOTRANSFERASE
Function / homology
Function and homology information


regulation of cell activation / histone H2AXY142 kinase activity / interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid 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 / interleukin-12 receptor complex ...regulation of cell activation / histone H2AXY142 kinase activity / interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid 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 / interleukin-12 receptor complex / interleukin-23 receptor complex / 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 / histone H3Y41 kinase activity / interleukin-5-mediated signaling pathway / interleukin-23-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / Interleukin-23 signaling / positive regulation of leukocyte proliferation / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / positive regulation of MHC class II biosynthetic process / acetylcholine receptor binding / positive regulation of natural killer cell proliferation / positive regulation of platelet activation / growth hormone receptor binding / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / positive regulation of epithelial cell apoptotic process / regulation of receptor signaling pathway via JAK-STAT / positive regulation of cell-substrate adhesion / extrinsic component of cytoplasmic side of plasma membrane / axon regeneration / extrinsic component of plasma membrane / response to hydroperoxide / Interleukin-20 family signaling / growth hormone receptor signaling pathway / Interleukin-6 signaling / negative regulation of cardiac muscle cell apoptotic process / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cell-cell adhesion / peptide hormone receptor binding / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / MAPK1 (ERK2) activation / Prolactin receptor signaling / positive regulation of interleukin-17 production / response to amine / signaling receptor activator activity / regulation of cell-cell adhesion / mesoderm development / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / response to tumor necrosis factor / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / Erythropoietin activates RAS / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / actin filament polymerization / negative regulation of cytokine production involved in inflammatory response / endomembrane system / post-translational protein modification / cellular response to dexamethasone stimulus / SH2 domain binding / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte 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 / : ...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 / : / SH2 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 / 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-EKT / Tyrosine-protein kinase JAK2 / Tyrosine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsDekker, C. / Hinniger, A.
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
DepositionMar 24, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2019Provider: repository / Type: Initial release
Revision 1.1May 8, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: 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

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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)63,89516
Polymers62,3402
Non-polymers1,55614
Water8,323462
1
A: Tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,07210
Polymers31,1701
Non-polymers9029
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8246
Polymers31,1701
Non-polymers6545
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.310, 56.270, 61.130
Angle α, β, γ (deg.)90.010, 101.440, 108.440
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Tyrosine-protein kinase


Mass: 31169.807 Da / Num. of mol.: 2 / Fragment: pseudokinase domain, UNP residues 537-808 / Mutation: V617F, 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-EKT / 2-[[3,5-bis(fluoranyl)-4-oxidanyl-phenyl]amino]-5,7,7-trimethyl-8-(3-methylbutyl)pteridin-6-one


Mass: 405.442 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25F2N5O2
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 462 / 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: 2.37 Å3/Da / Density % sol: 48.11 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 24% PEG4000, 0.1M Magnesium Acetate, 0.1M Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.978 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 29, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.6→53.261 Å / Num. obs: 71269 / % possible obs: 94.3 % / Redundancy: 1.795 % / Biso Wilson estimate: 24.826 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.063 / Rrim(I) all: 0.09 / Χ2: 0.956 / Net I/σ(I): 7.27
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.6-1.641.8410.591.3252050.4960.83493.3
1.64-1.691.8320.5051.5150450.5820.71493.1
1.69-1.741.8030.4341.7849590.6830.61393.5
1.74-1.791.7690.3612.0748030.7520.51193.3
1.79-1.851.6810.272.5747060.8330.38293.5
1.85-1.911.7610.2013.4145020.8970.28593.8
1.91-1.981.8570.1694.4743980.9250.2494.7
1.98-2.071.840.1245.6442470.960.17594.9
2.07-2.161.8240.1096.4341010.9690.15495
2.16-2.261.7890.0837.9538740.980.11794.4
2.26-2.391.6460.0718.4837350.9850.195.5
2.39-2.531.840.06910.0235130.9850.09895.2
2.53-2.71.8630.05711.3433260.9890.0895.4
2.7-2.921.8370.05112.8630790.9910.07295.6
2.92-3.21.7870.04514.2328240.9920.06494.1
3.2-3.581.6260.03716.0525270.9950.05294.2
3.58-4.131.8860.03319.9622360.9950.04694.9
4.13-5.061.8640.0321.0918850.9960.04294.7
5.06-7.161.6610.0318.8114970.9950.04296.1
7.16-53.2611.9750.02423.68070.9970.03595.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4fvr

4fvr


Resolution: 1.6→42.96 Å / Cross valid method: THROUGHOUT / Details: BUSTER 2.11.7 used
RfactorNum. reflection% reflectionSelection details
Rfree0.22 3563 5 %RANDOM
Rwork0.195 ---
obs0.196 71257 94.3 %-
Displacement parametersBiso max: 89 Å2 / Biso mean: 23.8146 Å2 / Biso min: 7.19 Å2
Refinement stepCycle: LAST / Resolution: 1.6→42.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4245 0 106 462 4813

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