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- PDB-3rvg: Crystals structure of Jak2 with a 1-amino-5H-pyrido[4,3-b]indol-4... -

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Basic information

Entry
Database: PDB / ID: 3rvg
TitleCrystals structure of Jak2 with a 1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitor
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Tyrosine Kinase / Janus Kinase 2 / Enzyme Inhibitors / 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 / : / 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 / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / 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 / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / response to interleukin-12 / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / positive regulation of platelet aggregation / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / positive regulation of platelet activation / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / positive regulation of signaling receptor activity / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / growth hormone receptor signaling pathway / axon regeneration / response to hydroperoxide / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / peptide hormone receptor binding / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / negative regulation of DNA binding / response to amine / : / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of interleukin-17 production / mesoderm development / MAPK1 (ERK2) activation / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / platelet-derived growth factor receptor signaling pathway / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / type II interferon-mediated signaling pathway / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / 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 / post-translational protein modification / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / 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 / : ...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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-17P / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.498 Å
AuthorsLim, J. / Taoka, B. / Otte, R.D. / Spencer, K. / Dinsmore, C.J. / Altman, M.D. / Chan, G. / Rosenstein, C. / Sharma, S. / Su, H.P. ...Lim, J. / Taoka, B. / Otte, R.D. / Spencer, K. / Dinsmore, C.J. / Altman, M.D. / Chan, G. / Rosenstein, C. / Sharma, S. / Su, H.P. / Szewczak, A.A. / Xu, L. / Yin, H. / Zugay-Murphy, J. / Marshall, C.G. / Young, J.R.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Discovery of 1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus kinase 2 (JAK2) for the treatment of myeloproliferative disorders.
Authors: Lim, J. / Taoka, B. / Otte, R.D. / Spencer, K. / Dinsmore, C.J. / Altman, M.D. / Chan, G. / Rosenstein, C. / Sharma, S. / Su, H.P. / Szewczak, A.A. / Xu, L. / Yin, H. / Zugay-Murphy, J. / ...Authors: Lim, J. / Taoka, B. / Otte, R.D. / Spencer, K. / Dinsmore, C.J. / Altman, M.D. / Chan, G. / Rosenstein, C. / Sharma, S. / Su, H.P. / Szewczak, A.A. / Xu, L. / Yin, H. / Zugay-Murphy, J. / Marshall, C.G. / Young, J.R.
History
DepositionMay 6, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 21, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2017Group: Refinement description / Category: software
Revision 1.2Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1842
Polymers35,7961
Non-polymers3881
Water1267
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)124.433, 124.433, 36.734
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

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


Mass: 35795.785 Da / Num. of mol.: 1 / Fragment: UNP residues 835-1132
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, EC: 2.7.1.112, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-17P / 1-(cyclohexylamino)-7-(1-methyl-1H-pyrazol-4-yl)-5H-pyrido[4,3-b]indole-4-carboxamide


Mass: 388.466 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O
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: 2.29 Å3/Da / Density % sol: 46.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M HEPES pH 7.5, 100mM Ammonium Sulfate, 33.5% PEG 3350, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Mar 26, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. all: 11589 / Num. obs: 11558 / Biso Wilson estimate: 43.14 Å2

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Processing

Software
NameVersionClassificationNB
PHENIX1.6.4_486refinement
PDB_EXTRACT3.1data extraction
JDirectordata collection
DENZOdata reduction
SCALEPACKdata scaling
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.498→31.632 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.45 / σ(F): 1.34 / Phase error: 31.79 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3 606 5.24 %Random
Rwork0.2208 ---
obs0.2251 11558 99.72 %-
all-11589 --
Solvent computationShrinkage radii: 0.72 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 30.588 Å2 / ksol: 0.307 e/Å3
Displacement parametersBiso max: 102.9 Å2 / Biso mean: 43.7839 Å2 / Biso min: 19.14 Å2
Baniso -1Baniso -2Baniso -3
1-0.1112 Å2-0 Å2-0 Å2
2--0.1112 Å2-0 Å2
3----0.2224 Å2
Refinement stepCycle: LAST / Resolution: 2.498→31.632 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2363 0 29 7 2399
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082447
X-RAY DIFFRACTIONf_angle_d1.2313301
X-RAY DIFFRACTIONf_chiral_restr0.075343
X-RAY DIFFRACTIONf_plane_restr0.005418
X-RAY DIFFRACTIONf_dihedral_angle_d18.15926
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.498-2.74930.37091510.29182689284099
2.7493-3.14680.32651590.244226982857100
3.1468-3.96340.30021370.211827492886100
3.9634-31.63450.27251590.201928142973100

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