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- PDB-6vgl: JAK2 JH1 in complex with ruxolitinib -

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Basic information

Entry
Database: PDB / ID: 6vgl
TitleJAK2 JH1 in complex with ruxolitinib
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Janus associated kinase / JAK2 / kinase domain / JH1 / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


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 ...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 / 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 / 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 / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / endosome lumen / positive regulation of receptor signaling pathway via JAK-STAT
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 / 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-RXT / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
Model detailsCo-crystal structure of JAK2 JH1 and ruxolitinib complex
AuthorsDavis, R.R. / Schonbrunn, E.
Funding support United States, 1items
OrganizationGrant numberCountry
Leukemia & Lymphoma Society8012-18 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof.
Authors: Davis, R.R. / Li, B. / Yun, S.Y. / Chan, A. / Nareddy, P. / Gunawan, S. / Ayaz, M. / Lawrence, H.R. / Reuther, G.W. / Lawrence, N.J. / Schonbrunn, E.
History
DepositionJan 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 10, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)147,0478
Polymers145,8224
Non-polymers1,2254
Water13,403744
1
D: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7622
Polymers36,4551
Non-polymers3061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7622
Polymers36,4551
Non-polymers3061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7622
Polymers36,4551
Non-polymers3061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7622
Polymers36,4551
Non-polymers3061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.960, 70.440, 112.940
Angle α, β, γ (deg.)90.000, 90.440, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and resid 843 through 1131)
21(chain B and resid 843 through 1131)
31chain C
41chain D

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLN / Beg label comp-ID: GLN / End auth comp-ID: ALA / End label comp-ID: ALA / Auth seq-ID: 843 - 1131 / Label seq-ID: 19 - 307

Dom-IDSelection detailsAuth asym-IDLabel asym-ID
1(chain A and resid 843 through 1131)AD
2(chain B and resid 843 through 1131)BB
3chain CCC
4chain DDA

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Components

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


Mass: 36455.441 Da / Num. of mol.: 4 / Fragment: JAK2 kinase domain (UNP residues 840-1132)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Plasmid: pcDNA 3.3 / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-RXT / (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile / Ruxolitinib


Mass: 306.365 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H18N6 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 744 / 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: 3.05 Å3/Da / Density % sol: 59.72 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.1 M Bis-Tris, pH 5.5, 0.2 M sodium chloride, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 4, 2019
RadiationMonochromator: Rosenbaum-Rock double crystal Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→52.815 Å / Num. obs: 138102 / % possible obs: 99.6 % / Redundancy: 3.73 % / Biso Wilson estimate: 36.3 Å2 / CC1/2: 1 / Rrim(I) all: 0.078 / Net I/σ(I): 11.9
Reflection shellResolution: 1.9→1.95 Å / Mean I/σ(I) obs: 0.8 / Num. unique obs: 10192 / CC1/2: 0.34 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.14-3260_3260refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2XA4

2xa4


Resolution: 1.9→52.815 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 24.61
RfactorNum. reflection% reflection
Rfree0.2168 6904 5 %
Rwork0.1803 --
obs0.1821 138068 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 128.77 Å2 / Biso mean: 44.5967 Å2 / Biso min: 22.02 Å2
Refinement stepCycle: final / Resolution: 1.9→52.815 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9758 0 92 744 10594
Biso mean--31.35 48.29 -
Num. residues----1181
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5923X-RAY DIFFRACTION13.356TORSIONAL
12B5923X-RAY DIFFRACTION13.356TORSIONAL
13C5923X-RAY DIFFRACTION13.356TORSIONAL
14D5923X-RAY DIFFRACTION13.356TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.9-1.92160.4132290.37854347100
1.9216-1.94420.39592280.35514342100
1.9442-1.96790.32262290.33794356100
1.9679-1.99280.34342300.3234365100
1.9928-2.0190.3682310.29044377100
2.019-2.04670.30922290.27164355100
2.0467-2.07590.27662300.25094376100
2.0759-2.10690.26832280.23974326100
2.1069-2.13980.29962310.23664393100
2.1398-2.17490.25162300.22794358100
2.1749-2.21240.25872300.21484376100
2.2124-2.25270.24532290.21414358100
2.2527-2.2960.26472300.21234352100
2.296-2.34290.25132300.20574373100
2.3429-2.39380.25272280.20574326100
2.3938-2.44950.27642300.19754383100
2.4495-2.51070.24152300.1957436999
2.5107-2.57860.2592280.1944433099
2.5786-2.65450.23132300.1884435899
2.6545-2.74020.22532280.1722435199
2.7402-2.83810.20652310.1787437599
2.8381-2.95170.20482310.1808439599
2.9517-3.0860.23532290.181434399
3.086-3.24870.20762290.1732435599
3.2487-3.45220.2172300.1636438099
3.4522-3.71870.19292330.1566441199
3.7187-4.09280.15952290.1447434998
4.0928-4.68480.16962320.1386441199
4.6848-5.9010.20432330.1584443100
5.901-52.8150.17922390.1643453199

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