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- PDB-3ugc: Structural basis of Jak2 inhibition by the type II inhibtor NVP-BBT594 -

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Basic information

Entry
Database: PDB / ID: 3ugc
TitleStructural basis of Jak2 inhibition by the type II inhibtor NVP-BBT594
ComponentsTyrosine-protein kinase JAK2
KeywordsTransferase/transferase inhibitor / Small molecule 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 / interleukin-12 receptor complex / activation of Janus kinase activity / 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 / Interleukin-12 signaling / positive regulation of signaling receptor activity / 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 / growth hormone receptor signaling pathway / peptide hormone receptor binding / 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 / mesoderm development / positive regulation of natural killer cell proliferation / 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 / extrinsic apoptotic signaling pathway / positive regulation of 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 / extrinsic component of cytoplasmic side of plasma membrane / actin filament polymerization / 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-046 / MALONATE ION / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.34 Å
AuthorsScheufler, C. / Tavares, G.A. / Manley, P.W. / Pissot-Soldermann, C. / Kroemer, M.
CitationJournal: Cancer Discov / Year: 2012
Title: Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent.
Authors: Andraos, R. / Qian, Z. / Bonenfant, D. / Rubert, J. / Vangrevelinghe, E. / Scheufler, C. / Marque, F. / Regnier, C.H. / De Pover, A. / Ryckelynck, H. / Bhagwat, N. / Koppikar, P. / Goel, A. ...Authors: Andraos, R. / Qian, Z. / Bonenfant, D. / Rubert, J. / Vangrevelinghe, E. / Scheufler, C. / Marque, F. / Regnier, C.H. / De Pover, A. / Ryckelynck, H. / Bhagwat, N. / Koppikar, P. / Goel, A. / Wyder, L. / Tavares, G. / Baffert, F. / Pissot-Soldermann, C. / Manley, P.W. / Gaul, C. / Voshol, H. / Levine, R.L. / Sellers, W.R. / Hofmann, F. / Radimerski, T.
History
DepositionNov 2, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 16, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 4, 2012Group: Non-polymer description
Revision 1.2Aug 29, 2012Group: Database references
Revision 1.3Apr 11, 2018Group: Data collection / Structure summary / Category: entity / Item: _entity.src_method
Revision 1.4Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_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)35,2023
Polymers34,5311
Non-polymers6722
Water4,954275
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)106.970, 69.390, 50.800
Angle α, β, γ (deg.)90.00, 98.98, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 34530.527 Da / Num. of mol.: 1 / Fragment: unp residues 840-1132 / Mutation: Y1007F, Y1008F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: PACG2TTEV / Cell line (production host): SF9DE / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-046 / 5-{[6-(acetylamino)pyrimidin-4-yl]oxy}-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-2,3-dihydro-1H-indole-1-carboxamide


Mass: 569.578 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30F3N7O3
#3: Chemical ChemComp-MLI / MALONATE ION / Malonic acid


Mass: 102.046 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H2O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 275 / 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: 2.7 Å3/Da / Density % sol: 54.39 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 1.8M SODIUM MALONATE PH 6.0, 0.1M GLYCINE-PH 8.2, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 30, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.34→20 Å / Num. all: 79053 / Num. obs: 79053 / % possible obs: 96.1 % / Observed criterion σ(I): -3 / Redundancy: 3.4 % / Biso Wilson estimate: 18.8 Å2 / Rmerge(I) obs: 0.042 / Net I/σ(I): 17.4
Reflection shellResolution: 1.34→1.37 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.429 / Mean I/σ(I) obs: 3.3 / Num. unique all: 5739 / % possible all: 95

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Processing

Software
NameVersionClassification
PHASERphasing
BUSTER2.9.6refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2B7A
Resolution: 1.34→19.83 Å / Cor.coef. Fo:Fc: 0.9589 / Cor.coef. Fo:Fc free: 0.9524 / SU R Cruickshank DPI: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.1891 3953 5 %RANDOM
Rwork0.1761 ---
obs0.1768 79050 96.15 %-
Displacement parametersBiso mean: 18.98 Å2
Baniso -1Baniso -2Baniso -3
1--0.5179 Å20 Å2-1.113 Å2
2---0.3235 Å20 Å2
3---0.8414 Å2
Refine analyzeLuzzati coordinate error obs: 0.141 Å
Refinement stepCycle: LAST / Resolution: 1.34→19.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2239 0 48 275 2562
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012404HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.093240HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d886SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes67HARMONIC2
X-RAY DIFFRACTIONt_gen_planes339HARMONIC5
X-RAY DIFFRACTIONt_it2404HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.94
X-RAY DIFFRACTIONt_other_torsion65.6
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion287SEMIHARMONIC5
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_contact3061SEMIHARMONIC4
LS refinement shellResolution: 1.34→1.38 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2213 287 5.01 %
Rwork0.2211 5446 -
all0.2211 5733 -
obs-5446 96.15 %

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