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- PDB-5cxh: SYK catalytic domain complexed with a potent orally bioavailable ... -

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Basic information

Entry
Database: PDB / ID: 5cxh
TitleSYK catalytic domain complexed with a potent orally bioavailable thiazole inhibitor
ComponentsTyrosine-protein kinase SYK
KeywordsTransferase/Transferase 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 arachidonic acid secretion / cellular response to lectin / serotonin secretion by platelet / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / B cell receptor complex ...interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonic acid secretion / cellular response to lectin / serotonin secretion by platelet / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / B cell receptor complex / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation / neutrophil activation involved in immune response / 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 / positive regulation of killing of cells of another organism / regulation of phagocytosis / beta selection / macrophage activation involved in immune response / early phagosome / cellular response to molecule of fungal origin / leukotriene biosynthetic process / FLT3 signaling through SRC family kinases / regulation of tumor necrosis factor-mediated signaling pathway / cellular response to lipid / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / 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 / blood vessel morphogenesis / positive regulation of alpha-beta T cell differentiation / 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 / positive regulation of interleukin-4 production / Dectin-2 family / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / phospholipase binding / 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 / phosphatase binding / positive regulation of bone resorption / 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 / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of interleukin-12 production / phosphotyrosine residue binding / Integrin signaling / SH2 domain binding / FCERI mediated Ca+2 mobilization / B cell differentiation / FCGR3A-mediated IL10 synthesis / neutrophil chemotaxis / regulation of ERK1 and ERK2 cascade / 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 / calcium-mediated signaling / 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 / 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 / protein import into nucleus / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / positive regulation of peptidyl-tyrosine phosphorylation / integrin binding / DAP12 signaling
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-55M / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsLee, C.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.
Authors: Thoma, G. / Veenstra, S. / Strang, R. / Blanz, J. / Vangrevelinghe, E. / Berghausen, J. / Lee, C.C. / Zerwes, H.G.
History
DepositionJul 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2015Group: Database references
Revision 1.2Dec 16, 2015Group: Refinement description
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)34,0692
Polymers33,6701
Non-polymers3991
Water3,855214
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.000, 85.343, 90.076
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: 33669.762 Da / Num. of mol.: 1 / Fragment: Protein kinase domain residues 356-635 / Mutation: K467T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-55M / (4R)-4-[(1R)-1-{[6-(3,4-dimethoxyphenyl)[1,3]thiazolo[5,4-c]pyridin-4-yl]oxy}ethyl]pyrrolidin-2-one


Mass: 399.463 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N3O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 2.39 Å3/Da / Density % sol: 48.49 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.3
Details: 20% PEG3350, 0.2M potassium fluoride, no buffer pH 7.3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 24752 / % possible obs: 98.8 % / Redundancy: 3.2 % / Biso Wilson estimate: 23.59 Å2 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.061 / Rrim(I) all: 0.114 / Χ2: 0.931 / Net I/av σ(I): 11.675 / Net I/σ(I): 8.5 / Num. measured all: 79115
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.9730.52124070.7260.3450.6280.94398.9
1.97-2.053.10.36224320.8520.2360.4340.96498.6
2.05-2.143.10.28624550.8870.1850.3420.97999
2.14-2.253.20.22224310.9260.1440.2661.02199.1
2.25-2.393.30.17124320.9540.110.2040.95698.5
2.39-2.583.30.13724430.970.0880.1630.98698.1
2.58-2.843.30.10224760.9790.0650.1220.88298.7
2.84-3.253.30.0824840.9850.050.0950.82299.3
3.25-4.093.20.06825430.9890.0430.0810.84999.1
4.09-503.10.05326490.9920.0330.0620.93198.3

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
BUSTER-TNT2.11.2refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→39.83 Å / Cor.coef. Fo:Fc: 0.9494 / Cor.coef. Fo:Fc free: 0.927 / SU R Cruickshank DPI: 0.138 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.148 / SU Rfree Blow DPI: 0.129 / SU Rfree Cruickshank DPI: 0.125
RfactorNum. reflection% reflectionSelection details
Rfree0.2052 1242 5.08 %RANDOM
Rwork0.1746 ---
obs0.1761 24439 97.61 %-
Displacement parametersBiso max: 98.14 Å2 / Biso mean: 25.85 Å2 / Biso min: 9.43 Å2
Baniso -1Baniso -2Baniso -3
1-1.9745 Å20 Å20 Å2
2---0.7007 Å20 Å2
3----1.2737 Å2
Refine analyzeLuzzati coordinate error obs: 0.206 Å
Refinement stepCycle: final / Resolution: 1.9→39.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2243 0 28 214 2485
Biso mean--17.73 32.97 -
Num. residues----277
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d813SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes59HARMONIC2
X-RAY DIFFRACTIONt_gen_planes331HARMONIC5
X-RAY DIFFRACTIONt_it2328HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion278SEMIHARMONIC5
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_contact2867SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2328HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3148HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.16
X-RAY DIFFRACTIONt_other_torsion16.17
LS refinement shellResolution: 1.9→1.98 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2344 140 5.19 %
Rwork0.2058 2558 -
all0.2072 2698 -
obs--97.61 %
Refinement TLS params.Method: refined / Origin x: 3.9583 Å / Origin y: 10.6812 Å / Origin z: 19.4215 Å
111213212223313233
T-0.0406 Å2-0.0108 Å20.005 Å2--0.0579 Å20.0062 Å2---0.0664 Å2
L1.1159 °2-0.5179 °2-0.4591 °2-1.2894 °20.0722 °2--0.6172 °2
S-0.0505 Å °-0.0739 Å °0.0238 Å °0.0119 Å °0.0591 Å °-0.0177 Å °0.042 Å °0.0559 Å °-0.0086 Å °
Refinement TLS groupSelection details: { A|363 - A|639 }

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