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- PDB-4fyo: Crystal structure of spleen tyrosine kinase complexed with N-{(S)... -

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Basic information

Entry
Database: PDB / ID: 4fyo
TitleCrystal structure of spleen tyrosine kinase complexed with N-{(S)-1-[7-(3,4-Dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-pyrrolidin-3-yl}-terephthalamic acid
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase inhibitor / 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 / cellular response to lectin / positive regulation of interleukin-3 production / 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 / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / cellular response to lectin / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / B cell receptor complex / serotonin secretion by platelet / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation / leukocyte activation involved in immune response / neutrophil activation involved in immune response / positive regulation of mast cell cytokine production / positive regulation of mast cell degranulation / lymph vessel development / collagen-activated tyrosine kinase receptor signaling pathway / regulation of platelet activation / cell activation / positive regulation of killing of cells of another organism / beta selection / regulation of phagocytosis / cellular response to molecule of fungal origin / macrophage activation involved in immune response / early phagosome / FLT3 signaling through SRC family kinases / leukotriene biosynthetic process / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / cellular response to lipid / regulation of DNA-binding transcription factor activity / positive regulation of cell adhesion mediated by integrin / Fc epsilon receptor (FCERI) signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / Interleukin-2 signaling / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / positive regulation of B cell differentiation / T cell receptor complex / leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway involved in phagocytosis / mast cell degranulation / Dectin-2 family / positive regulation of interleukin-4 production / : / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / phospholipase binding / amyloid-beta clearance / positive regulation of receptor internalization / positive regulation of interleukin-10 production / cellular response to low-density lipoprotein particle stimulus / FCGR activation / positive regulation of type I interferon production / positive regulation of bone resorption / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / phosphatase binding / Signaling by CSF3 (G-CSF) / cell surface receptor protein tyrosine kinase signaling pathway / GPVI-mediated activation cascade / positive regulation of interleukin-12 production / neutrophil chemotaxis / positive regulation of TORC1 signaling / phosphotyrosine residue binding / positive regulation of calcium-mediated signaling / Integrin signaling / FCERI mediated Ca+2 mobilization / SH2 domain binding / 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 / positive regulation of interleukin-8 production / integrin-mediated signaling pathway / Regulation of signaling by CBL / animal organ morphogenesis / FCERI mediated MAPK activation / negative regulation of inflammatory response to antigenic stimulus / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / calcium-mediated signaling / non-membrane spanning protein tyrosine kinase activity / positive regulation of protein-containing complex assembly / Inactivation of CSF3 (G-CSF) signaling / receptor internalization / platelet activation / Regulation of actin dynamics for phagocytic cup formation / CLEC7A (Dectin-1) signaling / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / protein import into nucleus / cellular response to amyloid-beta / positive regulation of peptidyl-tyrosine phosphorylation / 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-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 / 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-0VF / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.4 Å
AuthorsKuglstatter, A. / Slade, M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Rational design of highly selective spleen tyrosine kinase inhibitors.
Authors: Lucas, M.C. / Goldstein, D.M. / Hermann, J.C. / Kuglstatter, A. / Liu, W. / Luk, K.C. / Padilla, F. / Slade, M. / Villasenor, A.G. / Wanner, J. / Xie, W. / Zhang, X. / Liao, C.
History
DepositionJul 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 30, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Refinement description / Category: software / Item: _software.name / _software.version
Revision 1.2Sep 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4052
Polymers33,8841
Non-polymers5211
Water5,350297
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.953, 85.563, 90.031
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 33884.004 Da / Num. of mol.: 1 / Fragment: RESIDUES 356-635, PROTEIN KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0VF / 4-{[(3S)-1-{7-[(3,4-dimethoxyphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}pyrrolidin-3-yl]carbamoyl}benzoic acid


Mass: 520.560 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24N6O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 297 / 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: 2.27 Å3/Da / Density % sol: 45.83 %
Crystal growTemperature: 283 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 28% PEG 4000, 0.2M ammonium sulfate, 0.1M HEPES, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 283K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: RAYONIX MX225HE / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 1.4→20.93 Å / Num. all: 61359 / Num. obs: 61191 / % possible obs: 99.2 % / Observed criterion σ(I): 3 / Redundancy: 7.1 % / Biso Wilson estimate: 18.3 Å2 / Rsym value: 0.083 / Net I/σ(I): 8.7
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 6.9 % / Mean I/σ(I) obs: 1.9 / Num. unique all: 8724 / % possible all: 98

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Processing

Software
NameVersionClassification
REFMAC5.5.0072refinement
CNSrefinement
MOSFLMdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 3FQE

3fqe


Resolution: 1.4→20.93 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.945 / SU B: 2.806 / SU ML: 0.052 / Cross valid method: THROUGHOUT / ESU R: 0.072 / ESU R Free: 0.071 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24017 3094 5.1 %RANDOM
Rwork0.2188 ---
obs0.21985 58024 99.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 24.42 Å2
Baniso -1Baniso -2Baniso -3
1--0.18 Å20 Å20 Å2
2---0.21 Å20 Å2
3---0.39 Å2
Refinement stepCycle: LAST / Resolution: 1.4→20.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2175 0 37 297 2509
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222271
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.9141.9813063
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5445264
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.55124.095105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.67515410
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.451512
X-RAY DIFFRACTIONr_chiral_restr0.0610.2315
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0211720
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.3611.51327
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.70522127
X-RAY DIFFRACTIONr_scbond_it0.9773944
X-RAY DIFFRACTIONr_scangle_it1.6364.5936
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 254 -
Rwork0.322 4124 -
obs--97.75 %
Refinement TLS params.Method: refined / Origin x: 3.784 Å / Origin y: 10.8716 Å / Origin z: 20.3502 Å
111213212223313233
T0.0118 Å2-0.0041 Å20.0083 Å2-0.0225 Å20.0033 Å2--0.0156 Å2
L0.5205 °2-0.0943 °2-0.3847 °2-0.6142 °2-0.0814 °2--0.3231 °2
S-0.0059 Å °-0.0636 Å °0.0142 Å °-0.0367 Å °0.0212 Å °0.0033 Å °0.0123 Å °0.0429 Å °-0.0152 Å °

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