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- PDB-4xg6: Crystal structure of an inhibitor-bound Syk -

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Basic information

Entry
Database: PDB / ID: 4xg6
TitleCrystal structure of an inhibitor-bound Syk
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Syk kinase / Inhibitor / Spleen tyrosine kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / positive regulation of interleukin-3 production / cellular response to lectin / B cell receptor complex / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation ...interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / positive regulation of interleukin-3 production / cellular response to lectin / B cell receptor complex / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation / serotonin secretion by platelet / leukocyte activation involved in immune response / neutrophil activation involved in immune response / lymph vessel development / positive regulation of mast cell degranulation / gamma-delta T cell differentiation / positive regulation of mast cell cytokine production / collagen-activated tyrosine kinase receptor signaling pathway / positive regulation of gamma-delta T cell differentiation / cell surface pattern recognition receptor signaling pathway / regulation of platelet activation / cell activation / beta selection / cellular response to molecule of fungal origin / FLT3 signaling through SRC family kinases / early phagosome / leukotriene biosynthetic process / regulation of phagocytosis / regulation of DNA-binding transcription factor activity / regulation of tumor necrosis factor-mediated signaling pathway / macrophage activation involved in immune response / interleukin-3-mediated signaling pathway / positive regulation of bone resorption / positive regulation of monocyte chemotactic protein-1 production / cellular response to lipid / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / positive regulation of cell adhesion mediated by integrin / positive regulation of B cell differentiation / leukocyte cell-cell adhesion / T cell receptor complex / mast cell degranulation / Dectin-2 family / positive regulation of interleukin-4 production / Fc-epsilon receptor signaling pathway / stimulatory C-type lectin receptor signaling pathway / Fc-gamma receptor signaling pathway involved in phagocytosis / amyloid-beta clearance / positive regulation of interleukin-10 production / positive regulation of receptor internalization / FCGR activation / cellular response to low-density lipoprotein particle stimulus / Role of LAT2/NTAL/LAB on calcium mobilization / positive regulation of type I interferon production / Role of phospholipids in phagocytosis / phosphatase binding / regulation of ERK1 and ERK2 cascade / phospholipase binding / GPVI-mediated activation cascade / Signaling by CSF3 (G-CSF) / positive regulation of superoxide anion generation / phosphotyrosine residue binding / neutrophil chemotaxis / positive regulation of interleukin-12 production / Integrin signaling / positive regulation of TORC1 signaling / FCERI mediated Ca+2 mobilization / SH2 domain binding / positive regulation of calcium-mediated signaling / FCGR3A-mediated IL10 synthesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / peptidyl-tyrosine phosphorylation / B cell differentiation / animal organ morphogenesis / integrin-mediated signaling pathway / positive regulation of interleukin-8 production / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Regulation of signaling by CBL / non-specific protein-tyrosine kinase / apoptotic signaling pathway / negative regulation of inflammatory response to antigenic stimulus / positive regulation of protein-containing complex assembly / calcium-mediated signaling / Inactivation of CSF3 (G-CSF) signaling / Regulation of actin dynamics for phagocytic cup formation / platelet activation / receptor internalization / positive regulation of interleukin-6 production / CLEC7A (Dectin-1) signaling / integrin binding / cellular response to amyloid-beta / protein import into nucleus / positive regulation of tumor necrosis factor production / kinase activity
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-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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-X6G / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsLee, S.J. / Choi, J. / Han, B.G. / Song, H. / Koh, J.S. / Lee, B.I.
CitationJournal: Febs J. / Year: 2016
Title: Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs
Authors: Lee, S.J. / Choi, J.S. / Han, B.G. / Kim, H.S. / Song, H.J. / Lee, J. / Nam, S. / Goh, S.H. / Kim, J.H. / Koh, J.S. / Lee, B.I.
History
DepositionDec 30, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 30, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2016Group: Database references
Revision 1.2Oct 19, 2016Group: Database references
Revision 1.3Nov 8, 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 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)34,2652
Polymers33,9011
Non-polymers3641
Water1,15364
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13520 Å2
Unit cell
Length a, b, c (Å)39.933, 88.267, 41.078
Angle α, β, γ (deg.)90.00, 91.37, 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: protein kinase domain, residues 356-635
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Plasmid: pVL1393 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-X6G / 1-[(1-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-3-methyl-1H-pyrazol-4-yl)methyl]azetidin-3-ol


Mass: 364.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 64 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.13 Å3/Da / Density % sol: 42.39 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 10~20%(v/v) PEG3350, 100 mM Tris-HCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 7A (6B, 6C1) / Wavelength: 1.2398 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Jul 29, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.2398 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 10345 / % possible obs: 92.7 % / Redundancy: 7 % / Net I/σ(I): 33.21
Reflection shellResolution: 2.4→2.44 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XG2

4xg2


Resolution: 2.4→44.13 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.929 / SU B: 8.698 / SU ML: 0.198 / Cross valid method: THROUGHOUT / ESU R: 0.925 / ESU R Free: 0.28 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23015 559 5.4 %RANDOM
Rwork0.1895 ---
obs0.19175 9770 92.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.939 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å2-0 Å2-1.2 Å2
2---2.14 Å2-0 Å2
3---2.51 Å2
Refinement stepCycle: 1 / Resolution: 2.4→44.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2200 0 27 64 2291
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192278
X-RAY DIFFRACTIONr_bond_other_d0.0030.022178
X-RAY DIFFRACTIONr_angle_refined_deg1.3371.9763073
X-RAY DIFFRACTIONr_angle_other_deg0.9193.0024983
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1235269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.60624.393107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.90615414
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6541512
X-RAY DIFFRACTIONr_chiral_restr0.0720.2322
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022546
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02521
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_it1.8994.1811082
X-RAY DIFFRACTIONr_mcbond_other1.8944.1791081
X-RAY DIFFRACTIONr_mcangle_it3.2396.261349
X-RAY DIFFRACTIONr_mcangle_other3.2386.2631350
X-RAY DIFFRACTIONr_scbond_it1.7224.4151196
X-RAY DIFFRACTIONr_scbond_other1.7214.4141197
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.0496.5341723
X-RAY DIFFRACTIONr_long_range_B_refined5.26532.8622613
X-RAY DIFFRACTIONr_long_range_B_other5.25132.8582606
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.402→2.465 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 24 -
Rwork0.245 419 -
obs--54.49 %

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