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- PDB-4rss: Crystal structure of tyrosine-protein kinase SYK with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4rss
TitleCrystal structure of tyrosine-protein kinase SYK with an inhibitor
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / 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 / macrophage activation involved in immune response / beta selection / regulation of phagocytosis / positive regulation of killing of cells of another organism / cellular response to molecule of fungal origin / regulation of tumor necrosis factor-mediated signaling pathway / leukotriene biosynthetic process / FLT3 signaling through SRC family kinases / early phagosome / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / cellular response to lipid / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of cell adhesion mediated by integrin / regulation of DNA-binding transcription factor activity / 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 cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of interleukin-10 production / 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 / SH2 domain binding / phosphotyrosine residue binding / Integrin signaling / FCERI mediated Ca+2 mobilization / regulation of ERK1 and ERK2 cascade / FCGR3A-mediated IL10 synthesis / B cell differentiation / neutrophil chemotaxis / positive regulation of superoxide anion generation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of interleukin-8 production / integrin-mediated signaling pathway / calcium-mediated signaling / Regulation of signaling by CBL / positive regulation of protein-containing complex assembly / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / 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 / CLEC7A (Dectin-1) signaling / platelet activation / 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-4MG / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsLee, B.I. / Lee, S.J. / Choi, J.-S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors.
Authors: Choi, J.S. / Hwang, H.J. / Kim, S.W. / Lee, B.I. / Lee, J. / Song, H.J. / Koh, J.S. / Kim, J.H. / Lee, P.H.
History
DepositionNov 11, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 21, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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 SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3182
Polymers33,9011
Non-polymers4181
Water3,207178
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.964, 88.281, 40.850
Angle α, β, γ (deg.)90.00, 91.48, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 33900.965 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-4MG / 1-[(3-methyl-1-{2-[(1,2,3-trimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1H-pyrazol-4-yl)methyl]azetidin-3-ol


Mass: 417.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N7O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 178 / 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: 2.12 Å3/Da / Density % sol: 42.11 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 10-20% (v/v) PEG 3350, 100mM Tris-HCl (pH 8.5) , VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 29, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.83→50 Å / Num. obs: 24171 / % possible obs: 97 %
Reflection shellResolution: 1.83→1.86 Å / % possible all: 97.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.8.0049refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→44.14 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.911 / SU B: 3.578 / SU ML: 0.109 / Cross valid method: THROUGHOUT / ESU R: 0.17 / ESU R Free: 0.152 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24869 1210 5 %RANDOM
Rwork0.21189 ---
obs0.21375 22930 97.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.173 Å2
Baniso -1Baniso -2Baniso -3
1--0.26 Å2-0 Å2-0.8 Å2
2---1.33 Å2-0 Å2
3---1.63 Å2
Refinement stepCycle: LAST / Resolution: 1.83→44.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2188 0 31 178 2397
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192291
X-RAY DIFFRACTIONr_bond_other_d0.0020.022197
X-RAY DIFFRACTIONr_angle_refined_deg1.481.9773093
X-RAY DIFFRACTIONr_angle_other_deg0.8363.0025028
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0275269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.71624.057106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.515421
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2581513
X-RAY DIFFRACTIONr_chiral_restr0.0850.2322
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022542
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02526
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.1773.0021076
X-RAY DIFFRACTIONr_mcbond_other2.1782.9991075
X-RAY DIFFRACTIONr_mcangle_it3.3584.4871342
X-RAY DIFFRACTIONr_mcangle_other3.3574.491343
X-RAY DIFFRACTIONr_scbond_it2.4733.351215
X-RAY DIFFRACTIONr_scbond_other2.4723.351216
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.0344.8881749
X-RAY DIFFRACTIONr_long_range_B_refined6.43524.6072814
X-RAY DIFFRACTIONr_long_range_B_other6.34224.3042748
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.833→1.88 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 80 -
Rwork0.251 1730 -
obs--99.02 %

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