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- PDB-8rrq: Crystal structure of human SYK in complex with compound 24 -

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Basic information

Entry
Database: PDB / ID: 8rrq
TitleCrystal structure of human SYK in complex with compound 24
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / inhibitor / kinase
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 / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / cellular response to lectin / B cell receptor complex / regulation of platelet aggregation ...interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / cellular response to lectin / B cell receptor complex / regulation of platelet aggregation / Toll-like receptor binding / serotonin secretion by platelet / positive regulation of alpha-beta T cell proliferation / leukocyte activation involved in immune response / positive regulation of mast cell cytokine production / neutrophil activation involved in immune response / cell surface pattern recognition receptor signaling pathway / positive regulation of mast cell degranulation / lymph vessel development / collagen-activated tyrosine kinase 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 / macrophage activation involved in immune response / regulation of tumor necrosis factor-mediated signaling pathway / interleukin-3-mediated signaling pathway / positive regulation of monocyte chemotactic protein-1 production / cellular response to lipid / regulation of DNA-binding transcription factor activity / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of cell adhesion mediated by integrin / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / 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 / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / Fc-gamma receptor signaling pathway involved in phagocytosis / phospholipase binding / amyloid-beta clearance / positive regulation of interleukin-10 production / positive regulation of receptor internalization / cellular response to low-density lipoprotein particle stimulus / FCGR activation / Role of LAT2/NTAL/LAB on calcium mobilization / positive regulation of type I interferon production / Role of phospholipids in phagocytosis / positive regulation of bone resorption / phosphatase binding / regulation of ERK1 and ERK2 cascade / Signaling by CSF3 (G-CSF) / GPVI-mediated activation cascade / neutrophil chemotaxis / phosphotyrosine residue binding / positive regulation of interleukin-12 production / positive regulation of TORC1 signaling / Integrin signaling / FCERI mediated Ca+2 mobilization / B cell differentiation / SH2 domain binding / FCGR3A-mediated IL10 synthesis / positive regulation of calcium-mediated signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of superoxide anion generation / animal organ morphogenesis / integrin-mediated signaling pathway / positive regulation of interleukin-8 production / non-membrane spanning protein tyrosine kinase activity / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Regulation of signaling by CBL / non-specific protein-tyrosine kinase / positive regulation of protein-containing complex assembly / apoptotic signaling pathway / negative regulation of inflammatory response to antigenic stimulus / calcium-mediated signaling / Inactivation of CSF3 (G-CSF) signaling / peptidyl-tyrosine phosphorylation / receptor internalization / Regulation of actin dynamics for phagocytic cup formation / platelet activation / positive regulation of interleukin-6 production / CLEC7A (Dectin-1) signaling / cellular response to amyloid-beta / protein import into nucleus / positive regulation of tumor necrosis factor production / kinase activity / integrin binding
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsCanevari, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Discovery and optimization of 4-pyrazolyl-2-aminopyrimidine derivatives as potent spleen tyrosine kinase (SYK) inhibitors.
Authors: Cervi, G. / D'Alessio, R. / Bindi, S. / Buffa, L. / Burocchi, A. / Canevari, G. / Modugno, M. / Motto, I. / Saturno, G. / Orsini, P.
History
DepositionJan 23, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Other / Structure summary
Category: pdbx_database_status / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_database_status.status_code_sf / _pdbx_entry_details.has_protein_modification

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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)33,3793
Polymers32,8681
Non-polymers5122
Water3,207178
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-0 kcal/mol
Surface area13230 Å2
Unit cell
Length a, b, c (Å)39.204, 87.344, 40.048
Angle α, β, γ (deg.)90.000, 92.159, 90.000
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: 32867.664 Da / Num. of mol.: 1
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-A1H2W / N-[(1S,2R)-2-azanylcyclohexyl]-5-[2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl]-2-methyl-pyrazole-3-carboxamide


Mass: 419.523 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.08 Å3/Da / Density % sol: 41 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.5
Details: 20% PEG 3350, 0.1 M bis tris propane pH 6.5, 0.2 M Na formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9796 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 21, 2017 / Details: Toroidal mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9796 Å / Relative weight: 1
ReflectionResolution: 1.6→43.67 Å / Num. obs: 34990 / % possible obs: 98.7 % / Redundancy: 2 % / CC1/2: 1 / Rmerge(I) obs: 0.019 / Χ2: 0.85 / Net I/σ(I): 17.4
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 2 % / Rmerge(I) obs: 0.318 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1625 / CC1/2: 0.823 / % possible all: 91.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→43.67 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.961 / SU B: 1.948 / SU ML: 0.066 / Cross valid method: FREE R-VALUE / ESU R: 0.091 / ESU R Free: 0.092
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2107 1746 4.99 %
Rwork0.1766 33244 -
all0.178 --
obs-34990 98.513 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 25.887 Å2
Baniso -1Baniso -2Baniso -3
1-0.011 Å2-0 Å21.279 Å2
2---1.001 Å2-0 Å2
3---0.891 Å2
Refinement stepCycle: LAST / Resolution: 1.6→43.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2143 0 37 178 2358
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0122248
X-RAY DIFFRACTIONr_bond_other_d0.0020.0162064
X-RAY DIFFRACTIONr_angle_refined_deg1.7481.6633041
X-RAY DIFFRACTIONr_angle_other_deg0.6191.5844794
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2975272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg12.2171012
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.46610394
X-RAY DIFFRACTIONr_dihedral_angle_6_deg17.4551096
X-RAY DIFFRACTIONr_chiral_restr0.090.2321
X-RAY DIFFRACTIONr_chiral_restr_other0.8490.28
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022514
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02455
X-RAY DIFFRACTIONr_nbd_refined0.2220.2431
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1880.21927
X-RAY DIFFRACTIONr_nbtor_refined0.1880.21082
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.21218
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1650.2120
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0020.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1270.212
X-RAY DIFFRACTIONr_nbd_other0.1950.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1370.222
X-RAY DIFFRACTIONr_mcbond_it2.3482.5731076
X-RAY DIFFRACTIONr_mcbond_other2.3392.5721076
X-RAY DIFFRACTIONr_mcangle_it3.1563.8511343
X-RAY DIFFRACTIONr_mcangle_other3.1553.8531344
X-RAY DIFFRACTIONr_scbond_it3.8633.0251172
X-RAY DIFFRACTIONr_scbond_other3.8623.0281173
X-RAY DIFFRACTIONr_scangle_it5.8144.3871695
X-RAY DIFFRACTIONr_scangle_other5.8124.3891696
X-RAY DIFFRACTIONr_lrange_it7.3641.4192620
X-RAY DIFFRACTIONr_lrange_other7.3641.4372621
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.6420.2851360.2562304X-RAY DIFFRACTION93.415
1.642-1.6860.2711780.2332346X-RAY DIFFRACTION98.6708
1.686-1.7350.2841000.2232329X-RAY DIFFRACTION98.0226
1.735-1.7890.2941220.2062224X-RAY DIFFRACTION97.75
1.789-1.8470.2471170.2032209X-RAY DIFFRACTION99.4017
1.847-1.9120.2331130.1982116X-RAY DIFFRACTION98.5847
1.912-1.9840.214990.1852053X-RAY DIFFRACTION98.3547
1.984-2.0650.2031250.1761945X-RAY DIFFRACTION98.8067
2.065-2.1560.2221130.1821876X-RAY DIFFRACTION99.5496
2.156-2.2610.227870.1861815X-RAY DIFFRACTION99.0625
2.261-2.3830.193670.1741763X-RAY DIFFRACTION99.026
2.383-2.5270.202700.1581649X-RAY DIFFRACTION99.2494
2.527-2.7010.223750.1761540X-RAY DIFFRACTION99.2624
2.701-2.9170.193860.1751443X-RAY DIFFRACTION99.5443
2.917-3.1940.219750.1811318X-RAY DIFFRACTION99.3581
3.194-3.5680.244380.1641237X-RAY DIFFRACTION99.8434
3.568-4.1160.164420.1471069X-RAY DIFFRACTION99.552
4.116-5.0290.163440.147908X-RAY DIFFRACTION98.9605
5.029-7.0660.208440.201682X-RAY DIFFRACTION99.1803
7.066-43.670.203150.194419X-RAY DIFFRACTION99.3135

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