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- PDB-8rrz: Crystal structure of SYK kinase in complex with compound 1 -

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Basic information

Entry
Database: PDB / ID: 8rrz
TitleCrystal structure of SYK kinase in complex with compound 1
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / kinase / inhibitor
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 / beta selection / regulation of phagocytosis / macrophage activation involved in immune response / positive regulation of killing of cells of another organism / leukotriene biosynthetic process / cellular response to molecule of fungal origin / regulation of tumor necrosis factor-mediated signaling pathway / FLT3 signaling through SRC family kinases / early phagosome / interleukin-3-mediated signaling pathway / cellular response to lipid / positive regulation of monocyte chemotactic protein-1 production / 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 / 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 interleukin-10 production / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / 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 / phosphotyrosine residue binding / SH2 domain binding / Integrin signaling / FCERI mediated Ca+2 mobilization / neutrophil chemotaxis / 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 / integrin-mediated signaling pathway / positive regulation of interleukin-8 production / calcium-mediated signaling / Regulation of signaling by CBL / positive regulation of protein-containing complex assembly / 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 / Inactivation of CSF3 (G-CSF) signaling / receptor internalization / Regulation of actin dynamics for phagocytic cup formation / platelet activation / CLEC7A (Dectin-1) signaling / 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 / 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: 1.75 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 24, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release

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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)33,5034
Polymers32,8681
Non-polymers6363
Water2,324129
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area370 Å2
ΔGint-0 kcal/mol
Surface area12670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.085, 84.859, 40.845
Angle α, β, γ (deg.)90.000, 99.329, 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-A1H2Y / N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide / ~{N}-[(2~{S})-1-(azetidin-1-yl)propan-2-yl]-5-[2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl]-2-methyl-pyrazole-3-carboxamide


Mass: 451.521 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 129 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.09 Å3/Da / Density % sol: 41.03 %
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: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Dec 3, 2018 / Details: CRL
RadiationMonochromator: C(110) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.75→42.43 Å / Num. obs: 26808 / % possible obs: 98.6 % / Redundancy: 2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.025 / Rpim(I) all: 0.025 / Rrim(I) all: 0.034 / Χ2: 0.96 / Net I/σ(I): 17.7
Reflection shellResolution: 1.75→1.78 Å / Redundancy: 2 % / Rmerge(I) obs: 0.32 / Num. unique obs: 1460 / CC1/2: 0.881 / Rpim(I) all: 0.32 / Rrim(I) all: 0.453 / Χ2: 0.92 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→39.586 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.948 / SU B: 2.665 / SU ML: 0.083 / Cross valid method: FREE R-VALUE / ESU R: 0.123 / ESU R Free: 0.116
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2145 1339 4.995 %
Rwork0.1802 25469 -
all0.182 --
obs-26808 98.562 %
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: 27.308 Å2
Baniso -1Baniso -2Baniso -3
1--1.573 Å2-0 Å2-0.698 Å2
2---1.559 Å2-0 Å2
3---3.189 Å2
Refinement stepCycle: LAST / Resolution: 1.75→39.586 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2138 0 45 129 2312
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0122256
X-RAY DIFFRACTIONr_bond_other_d0.0020.0162103
X-RAY DIFFRACTIONr_angle_refined_deg1.771.6673040
X-RAY DIFFRACTIONr_angle_other_deg0.7771.5874897
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5895265
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.5951012
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.90210413
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.68410100
X-RAY DIFFRACTIONr_chiral_restr0.0930.2318
X-RAY DIFFRACTIONr_chiral_restr_other0.8190.29
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022477
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02452
X-RAY DIFFRACTIONr_nbd_refined0.2740.2403
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2130.21984
X-RAY DIFFRACTIONr_nbtor_refined0.1850.21074
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0850.21186
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2150.2102
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0110.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.3730.217
X-RAY DIFFRACTIONr_nbd_other0.2860.247
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1880.214
X-RAY DIFFRACTIONr_mcbond_it2.6642.5951051
X-RAY DIFFRACTIONr_mcbond_other2.6552.5951051
X-RAY DIFFRACTIONr_mcangle_it3.6523.8651307
X-RAY DIFFRACTIONr_mcangle_other3.6513.871308
X-RAY DIFFRACTIONr_scbond_it4.0543.1081205
X-RAY DIFFRACTIONr_scbond_other4.0523.111206
X-RAY DIFFRACTIONr_scangle_it6.2084.491727
X-RAY DIFFRACTIONr_scangle_other6.2064.4921728
X-RAY DIFFRACTIONr_lrange_it7.43940.9222574
X-RAY DIFFRACTIONr_lrange_other7.4240.3622559
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.75-1.7950.698880.57318740.57819770.9330.93899.24130.57
1.795-1.8440.382790.31918750.32219690.9460.95199.23820.302
1.844-1.8980.251070.25117550.25118830.9550.9698.88480.232
1.898-1.9560.277810.19817630.20218660.9490.9798.8210.182
1.956-2.020.198880.16816680.16917820.9680.9898.5410.153
2.02-2.0910.207960.16415810.16717100.970.98398.07020.151
2.091-2.1690.206880.16315500.16516730.9770.98397.9080.153
2.169-2.2580.177730.16314870.16316170.9820.98496.4750.155
2.258-2.3580.213720.17114270.17315530.9690.98396.52290.163
2.358-2.4720.182620.16813050.16914570.9750.98493.82290.162
2.472-2.6060.231750.17613150.17914060.9670.98298.8620.17
2.606-2.7630.223670.17412680.17713350.9660.9821000.168
2.763-2.9530.146580.16711870.16612450.980.9841000.163
2.953-3.1880.217590.17111020.17411610.9730.9831000.171
3.188-3.490.206730.18110110.18310840.9710.981000.184
3.49-3.8980.235520.1649130.1679650.9660.9831000.171
3.898-4.4940.19520.1378250.148770.9780.9881000.147
4.494-5.4860.194340.1576850.1597190.980.9881000.172
5.486-7.6850.26270.25550.2025820.9580.9831000.212
7.685-39.5860.10180.2033220.23360.990.97698.21430.264

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