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- PDB-4yjr: SYK kinase domain in complex with inhibitor GTC000225 -

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Basic information

Entry
Database: PDB / ID: 4yjr
TitleSYK kinase domain in complex with inhibitor GTC000225
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / SYK / NON-RECEPTOR TYROSINE KINASE / SPLEEN TYROSINE KINASE / PHOSPHORYLATION / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
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 / positive regulation of killing of cells of another organism / regulation of phagocytosis / beta selection / macrophage activation involved in immune response / leukotriene biosynthetic process / cellular response to molecule of fungal origin / FLT3 signaling through SRC family kinases / early phagosome / regulation of tumor necrosis factor-mediated signaling pathway / 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 / positive regulation of interleukin-4 production / 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 receptor internalization / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / 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 / positive regulation of interleukin-12 production / phosphotyrosine residue binding / SH2 domain binding / Integrin signaling / FCERI mediated Ca+2 mobilization / B cell differentiation / neutrophil chemotaxis / FCGR3A-mediated IL10 synthesis / regulation of ERK1 and ERK2 cascade / 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 / Regulation of signaling by CBL / calcium-mediated signaling / FCERI mediated MAPK activation / FCGR3A-mediated phagocytosis / animal organ morphogenesis / cell surface receptor protein tyrosine kinase signaling pathway / 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 / Regulation of actin dynamics for phagocytic cup formation / platelet activation / 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-4DJ / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.32 Å
AuthorsSomers, D.O. / Neu, M. / Stuckey, J.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2011
Title: Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor.
Authors: Liddle, J. / Atkinson, F.L. / Barker, M.D. / Carter, P.S. / Curtis, N.R. / Davis, R.P. / Douault, C. / Dickson, M.C. / Elwes, D. / Garton, N.S. / Gray, M. / Hayhow, T.G. / Hobbs, C.I. / ...Authors: Liddle, J. / Atkinson, F.L. / Barker, M.D. / Carter, P.S. / Curtis, N.R. / Davis, R.P. / Douault, C. / Dickson, M.C. / Elwes, D. / Garton, N.S. / Gray, M. / Hayhow, T.G. / Hobbs, C.I. / Jones, E. / Leach, S. / Leavens, K. / Lewis, H.D. / McCleary, S. / Neu, M. / Patel, V.K. / Preston, A.G. / Ramirez-Molina, C. / Shipley, T.J. / Skone, P.A. / Smithers, N. / Somers, D.O. / Walker, A.L. / Watson, R.J. / Weingarten, G.G.
History
DepositionMar 3, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)33,2252
Polymers32,8111
Non-polymers4141
Water6,251347
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.430, 86.630, 40.270
Angle α, β, γ (deg.)90.000, 93.490, 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: 32810.605 Da / Num. of mol.: 1 / Fragment: UNP residues 355-635
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-4DJ / 3-(1H-indazol-4-yl{2-[(1-methyl-1H-indazol-5-yl)amino]pyrimidin-4-yl}amino)propan-1-ol


Mass: 414.463 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N8O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 347 / 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: 2.1 Å3/Da / Density % sol: 41.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 30% Jeffamine ED-2001, 10% Glycerol, 0.1M MES pH6.0, 5mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 28, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.25→29.128 Å / Num. obs: 74248 / % possible obs: 99.8 % / Redundancy: 3.6 % / Biso Wilson estimate: 13.3 Å2 / Rmerge(I) obs: 0.049 / Rsym value: 0.049 / Net I/av σ(I): 7.984 / Net I/σ(I): 13.8 / Num. measured all: 267412
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym valueNet I/σ(I) obs% possible all
1.25-1.323.30.4851.535693107090.4852.398.8
1.32-1.43.60.3482.137022102630.3483.5100
1.4-1.493.60.2193.33490196450.2195.6100
1.49-1.613.60.1385.23264989870.1389.1100
1.61-1.773.70.097.93018682690.0913.7100
1.77-1.983.70.05711.32740574670.05719.4100
1.98-2.283.70.03915.82442366050.03925.3100
2.28-2.83.70.035162078855890.03529.1100
2.8-3.953.70.03215.71607043500.03234.799.9
3.95-29.4633.50.03118.5827523640.03136.398.7

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Processing

Software
NameVersionClassification
MOSFLM6.2.4data reduction
SCALA3.2.5data scaling
BUSTER2.11.2refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: In-house SYK model

Resolution: 1.32→29 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.9498 / SU R Cruickshank DPI: 0.05 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.046 / SU Rfree Blow DPI: 0.048 / SU Rfree Cruickshank DPI: 0.048
RfactorNum. reflection% reflectionSelection details
Rfree0.1801 3179 5.03 %RANDOM
Rwork0.1555 ---
obs0.1568 63169 99.91 %-
Displacement parametersBiso max: 104.77 Å2 / Biso mean: 18.53 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--1.5359 Å20 Å2-0.5867 Å2
2--2.1778 Å20 Å2
3----0.6419 Å2
Refine analyzeLuzzati coordinate error obs: 0.146 Å
Refinement stepCycle: final / Resolution: 1.32→29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2172 0 53 347 2572
Biso mean--14.93 28.85 -
Num. residues----265
LS refinement shellResolution: 1.32→1.35 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2162 229 4.89 %
Rwork0.2007 4452 -
all0.2015 4681 -
obs--99.91 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.41510.35170.70900.39380.3112-0.0050.0040.0014-0.0298-0.0085-0.0068-0.0186-0.01920.01340.05480.014-0.0102-0.0331-0.0349-0.028327.642447.198727.4973
20.0964-0.32280.29651.03040.02640.5565-0.01550.0223-0.0028-0.0480.0024-0.0256-0.0549-0.02570.013-0.0021-0.00270.0086-0.0097-0.0075-0.016526.508836.109229.7914
30.8236-0.19120.27291.10540.0840.5274-0.00790.0226-0.00360.02950.0182-0.0413-0.0210.0138-0.0103-0.02580.0020.0112-0.0269-0.0061-0.026433.714223.627738.0506
40.7887-0.2269-0.13110.53780.20340.5120.00260.0004-0.03870.07860.0096-0.0490.01010.0357-0.01220.00970.0055-0.0068-0.0307-0.0014-0.017139.542215.703444.3408
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|364 - 407}A364 - 407
2X-RAY DIFFRACTION2{A|408 - 458}A408 - 458
3X-RAY DIFFRACTION3{A|459 - 570}A459 - 570
4X-RAY DIFFRACTION4{A|571 - 633}A571 - 633

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