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- PDB-5tr6: Discovery of TAK-659, an Orally Available Investigational Inhibit... -

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Basic information

Entry
Database: PDB / ID: 5tr6
TitleDiscovery of TAK-659, an Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase (SYK)
ComponentsTyrosine-protein kinase SYK
KeywordsTransferase/Transferase Inhibitor / Inhibitor / kinase / Leukemia / Lymphoma / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


serotonin secretion by platelet / interleukin-15 receptor binding / positive regulation of interleukin-3 production / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonic acid secretion / cellular response to lectin / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / B cell receptor complex ...serotonin secretion by platelet / interleukin-15 receptor binding / positive regulation of interleukin-3 production / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonic acid secretion / cellular response to lectin / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / B cell receptor complex / neutrophil activation involved in immune response / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation / leukocyte activation involved in immune response / positive regulation of mast cell cytokine production / regulation of platelet activation / lymph vessel development / collagen-activated tyrosine kinase receptor signaling pathway / cell activation / positive regulation of mast cell degranulation / beta selection / regulation of phagocytosis / positive regulation of killing of cells of another organism / macrophage activation involved in immune response / leukotriene biosynthetic process / cellular response to molecule of fungal origin / regulation of tumor necrosis factor-mediated signaling pathway / FLT3 signaling through SRC family kinases / early phagosome / interleukin-3-mediated signaling pathway / cellular response to lipid / positive regulation of monocyte chemotactic protein-1 production / regulation of DNA-binding transcription factor activity / positive regulation of cell adhesion mediated by integrin / positive regulation of granulocyte macrophage colony-stimulating factor production / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / T cell receptor complex / positive regulation of B cell differentiation / leukocyte cell-cell adhesion / mast cell degranulation / Fc-gamma receptor signaling pathway involved in phagocytosis / Dectin-2 family / Fc-epsilon receptor signaling pathway / stimulatory C-type lectin receptor signaling pathway / phospholipase binding / positive regulation of interleukin-10 production / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of receptor internalization / cellular response to low-density lipoprotein particle stimulus / FCGR activation / positive regulation of type I interferon production / positive regulation of interleukin-4 production / positive regulation of bone resorption / phosphatase binding / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / positive regulation of calcium-mediated signaling / Signaling by CSF3 (G-CSF) / negative regulation of inflammatory response to antigenic stimulus / GPVI-mediated activation cascade / positive regulation of TORC1 signaling / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of interleukin-12 production / phosphotyrosine residue binding / SH2 domain binding / Integrin signaling / FCERI mediated Ca+2 mobilization / neutrophil chemotaxis / regulation of ERK1 and ERK2 cascade / B cell differentiation / FCGR3A-mediated IL10 synthesis / positive regulation of superoxide anion generation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / integrin-mediated signaling pathway / positive regulation of interleukin-8 production / calcium-mediated signaling / Regulation of signaling by CBL / positive regulation of protein-containing complex assembly / FCERI mediated MAPK activation / FCGR3A-mediated phagocytosis / animal organ morphogenesis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / receptor internalization / Regulation of actin dynamics for phagocytic cup formation / platelet activation / CLEC7A (Dectin-1) signaling / positive regulation of interleukin-6 production / protein import into nucleus / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / integrin binding / positive regulation of tumor necrosis factor production
Similarity search - Function
Tyrosine-protein kinase, non-receptor SYK/ZAP-70 / Tyrosine-protein kinase SYK/ZAP-70, inter-SH2 domain superfamily / SYK/ZAP-70, N-terminal SH2 domain / 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 kinase, non-receptor SYK/ZAP-70 / Tyrosine-protein kinase SYK/ZAP-70, inter-SH2 domain superfamily / SYK/ZAP-70, N-terminal SH2 domain / 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. / 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-7KG / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.93 Å
AuthorsYano, J. / Jennings, A. / Lam, B. / Hoffman, I.D.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2016
Title: Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Authors: Lam, B. / Arikawa, Y. / Cramlett, J. / Dong, Q. / de Jong, R. / Feher, V. / Grimshaw, C.E. / Farrell, P.J. / Hoffman, I.D. / Jennings, A. / Jones, B. / Matuszkiewicz, J. / Miura, J. / ...Authors: Lam, B. / Arikawa, Y. / Cramlett, J. / Dong, Q. / de Jong, R. / Feher, V. / Grimshaw, C.E. / Farrell, P.J. / Hoffman, I.D. / Jennings, A. / Jones, B. / Matuszkiewicz, J. / Miura, J. / Miyake, H. / Natala, S.R. / Shi, L. / Takahashi, M. / Taylor, E. / Wyrick, C. / Yano, J. / Zalevsky, J. / Nie, Z.
History
DepositionOct 25, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 30, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 14, 2016Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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 SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1043
Polymers33,6981
Non-polymers4062
Water2,378132
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.941, 85.283, 90.283
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Tyrosine-protein kinase SYK / / Spleen tyrosine kinase / p72-Syk


Mass: 33697.836 Da / Num. of mol.: 1 / Fragment: UNP residues 356-635
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Production host: Baculovirus expression vector pFastBac1-HM / Strain (production host): sf9
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-7KG / 6-{[(1R,2S)-2-aminocyclohexyl]amino}-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one


Mass: 344.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21FN6O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 132 / 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: 2.43 Å3/Da / Density % sol: 49.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.1
Details: 0.7M Potassium Na Tartrate, 0.06M MES_Na, 0.04M MES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9764848 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 14, 2010
RadiationMonochromator: Single crystal, cylindrically bent, Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9764848 Å / Relative weight: 1
ReflectionResolution: 1.93→50 Å / Num. obs: 22613 / % possible obs: 99.49 % / Redundancy: 5.1 % / Net I/σ(I): 17.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
REFMAC5.8.0103refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 1.93→30 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.942 / SU B: 8.927 / SU ML: 0.112 / SU R Cruickshank DPI: 0.1625 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.163 / ESU R Free: 0.139
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2172 1204 5.1 %RANDOM
Rwork0.1933 ---
obs0.1945 22613 99.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 91.79 Å2 / Biso mean: 35.14 Å2 / Biso min: 15.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.4 Å20 Å2-0 Å2
2---2.25 Å2-0 Å2
3---2.66 Å2
Refinement stepCycle: final / Resolution: 1.93→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2217 0 29 132 2378
Biso mean--24.71 41.62 -
Num. residues----272
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192314
X-RAY DIFFRACTIONr_bond_other_d0.0010.022174
X-RAY DIFFRACTIONr_angle_refined_deg1.1211.9643127
X-RAY DIFFRACTIONr_angle_other_deg0.8535006
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5225276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.01924.037109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.9915413
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7261512
X-RAY DIFFRACTIONr_chiral_restr0.0660.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022587
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02542
X-RAY DIFFRACTIONr_mcbond_it0.9591.931092
X-RAY DIFFRACTIONr_mcbond_other0.961.9281091
X-RAY DIFFRACTIONr_mcangle_it1.6722.8841363
LS refinement shellResolution: 1.93→1.98 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 98 -
Rwork0.266 1563 -
all-1661 -
obs--95.46 %
Refinement TLS params.Method: refined / Origin x: -3.887 Å / Origin y: -10.474 Å / Origin z: 19.991 Å
111213212223313233
T0.0118 Å2-0.0059 Å2-0.0031 Å2-0.0943 Å2-0.0137 Å2--0.0082 Å2
L1.8748 °2-0.5311 °20.524 °2-3.5915 °2-0.1033 °2--1.0638 °2
S-0.0151 Å °0.0117 Å °0.0422 Å °-0.143 Å °0.016 Å °0.1111 Å °-0.0705 Å °-0.0524 Å °-0.0009 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A362 - 639
2X-RAY DIFFRACTION1A701 - 702
3X-RAY DIFFRACTION1A801 - 932

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