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- PDB-3q32: Structure of Janus kinase 2 with a pyrrolotriazine inhibitor -

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Basic information

Entry
Database: PDB / ID: 3q32
TitleStructure of Janus kinase 2 with a pyrrolotriazine inhibitor
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / ATP-binding / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / 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-J2I / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSack, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Pyrrolo[1,2-f]triazines as JAK2 inhibitors: Achieving potency and selectivity for JAK2 over JAK3.
Authors: Harikrishnan, L.S. / Kamau, M.G. / Wan, H. / Inghrim, J.A. / Zimmermann, K. / Sang, X. / Mastalerz, H.A. / Johnson, W.L. / Zhang, G. / Lombardo, L.J. / Poss, M.A. / Trainor, G.L. / Tokarski, ...Authors: Harikrishnan, L.S. / Kamau, M.G. / Wan, H. / Inghrim, J.A. / Zimmermann, K. / Sang, X. / Mastalerz, H.A. / Johnson, W.L. / Zhang, G. / Lombardo, L.J. / Poss, M.A. / Trainor, G.L. / Tokarski, J.S. / Lorenzi, M.V. / You, D. / Gottardis, M.M. / Baldwin, K.F. / Lippy, J. / Nirschl, D.S. / Qiu, R. / Miller, A.V. / Khan, J. / Sack, J.S. / Purandare, A.V.
History
DepositionDec 21, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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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)72,3564
Polymers71,3912
Non-polymers9652
Water1,62190
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1782
Polymers35,6961
Non-polymers4821
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1782
Polymers35,6961
Non-polymers4821
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)110.590, 110.590, 69.960
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

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


Mass: 35695.613 Da / Num. of mol.: 2 / Fragment: protein kinase 2 domain (UNP residues 839-1132)
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: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-J2I / 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-{4-[(3-methyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}piperazin-1-yl)ethanone


Mass: 482.486 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24F2N8O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 90 / 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: 3 Å3/Da / Density % sol: 58.95 %
Crystal growpH: 6.5
Details: 35% PEG3350, 0.1 M sodium chloride, 0.1 M MES, pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jun 12, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 29557 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 4.9 % / Biso Wilson estimate: 55.77 Å2 / Rmerge(I) obs: 0.078 / Net I/σ(I): 19
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.554 / Mean I/σ(I) obs: 3 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.9.7refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
AUTOBUSTERrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→49.46 Å / Cor.coef. Fo:Fc: 0.9211 / Cor.coef. Fo:Fc free: 0.9074 / SU R Cruickshank DPI: 0.326 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.311 / SU Rfree Blow DPI: 0.21 / SU Rfree Cruickshank DPI: 0.216
RfactorNum. reflection% reflectionSelection details
Rfree0.2097 649 2.21 %RANDOM
Rwork0.1777 ---
obs0.1785 29433 99.98 %-
Displacement parametersBiso mean: 55.14 Å2
Baniso -1Baniso -2Baniso -3
1--9.6748 Å20 Å20 Å2
2---9.6748 Å20 Å2
3---19.3496 Å2
Refine analyzeLuzzati coordinate error obs: 0.291 Å
Refinement stepCycle: LAST / Resolution: 2.5→49.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4879 0 70 90 5039
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015064HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.216831HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1827SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes142HARMONIC2
X-RAY DIFFRACTIONt_gen_planes709HARMONIC5
X-RAY DIFFRACTIONt_it5064HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.96
X-RAY DIFFRACTIONt_other_torsion21.7
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion605SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5761SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.59 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2962 55 1.91 %
Rwork0.2207 2831 -
all0.2219 2886 -
obs--99.98 %

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