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- PDB-4yjq: SYK kinase domain in complex with inhibitor GTC000224 -

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Basic information

Entry
Database: PDB / ID: 4yjq
TitleSYK kinase domain in complex with inhibitor GTC000224
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / SYK / NON-RECEPTOR TYROSINE KINASE / SPLEEN TYROSINE KINASE / PHOSPHORYLATION / 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 / gamma-delta T cell differentiation / serotonin secretion by platelet / positive regulation of interleukin-3 production / 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 / gamma-delta T cell differentiation / serotonin secretion by platelet / positive regulation of interleukin-3 production / 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 / leukocyte activation involved in immune response / neutrophil activation involved in immune response / positive regulation of mast cell cytokine production / lymph vessel development / regulation of platelet activation / 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 / FLT3 signaling through SRC family kinases / leukotriene biosynthetic process / 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 / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / 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 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 / 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-4DK / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.34 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)33,2522
Polymers32,8111
Non-polymers4411
Water5,819323
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.402, 86.841, 40.236
Angle α, β, γ (deg.)90.000, 93.420, 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-4DK / 3-[1H-indazol-4-yl(2-{[3-(4-methyl-1,3-oxazol-5-yl)phenyl]amino}pyrimidin-4-yl)amino]propan-1-ol


Mass: 441.485 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 323 / 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: 41.56 %
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: 1.27→29.488 Å / Num. obs: 70711 / % possible obs: 99.6 % / Redundancy: 3.7 % / Biso Wilson estimate: 14.43 Å2 / Rmerge(I) obs: 0.05 / Rsym value: 0.05 / Net I/av σ(I): 7.369 / Net I/σ(I): 14.1 / Num. measured all: 261221
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym valueNet I/σ(I) obs% possible all
1.27-1.343.60.4971.437125102180.4972.499
1.34-1.423.70.3292.13580096980.3293.799.4
1.42-1.523.70.2063.43390691900.2065.999.5
1.52-1.643.70.1285.73141285330.1289.599.9
1.64-1.83.70.0838.62925778950.08313.999.9
1.8-2.013.70.05512.12673471520.05520.1100
2.01-2.323.80.03915.92364862960.03926.4100
2.32-2.843.80.03714.72000853300.03730.199.9
2.84-4.023.70.03614.91537841370.0363499.8
4.02-29.4883.50.03516.7795322620.03535.598.4

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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: 1.34→29.48 Å / Cor.coef. Fo:Fc: 0.9643 / Cor.coef. Fo:Fc free: 0.9587 / SU R Cruickshank DPI: 0.053 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.049 / SU Rfree Blow DPI: 0.051 / SU Rfree Cruickshank DPI: 0.05
RfactorNum. reflection% reflectionSelection details
Rfree0.1835 3035 5.03 %RANDOM
Rwork0.161 ---
obs0.1622 60286 99.65 %-
Displacement parametersBiso max: 94.12 Å2 / Biso mean: 19.19 Å2 / Biso min: 3.19 Å2
Baniso -1Baniso -2Baniso -3
1--1.3454 Å20 Å2-0.6256 Å2
2--1.9357 Å20 Å2
3----0.5903 Å2
Refine analyzeLuzzati coordinate error obs: 0.154 Å
Refinement stepCycle: final / Resolution: 1.34→29.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2176 0 56 323 2555
Biso mean--15.54 29 -
Num. residues----266
LS refinement shellResolution: 1.34→1.38 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2332 220 5 %
Rwork0.1925 4184 -
all0.1945 4404 -
obs--99.65 %
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)
10.15960.46080.327300.35370.2887-0.00730.01970.007-0.0236-0.0192-0.0192-0.0276-0.01440.02650.03860.0070.0063-0.0125-0.0235-0.041627.832344.681425.8215
20.5727-0.12060.16071.2698-0.02230.5966-0.0353-0.00160.02850.02620.0231-0.0539-0.0872-0.03180.0122-0.02110.00590.0056-0.0268-0.0172-0.023330.382131.747837.6525
31.0656-0.45440.11141.12130.09530.78430.00570.0526-0.0068-0.0166-0.03460.02420.0340.05860.0289-0.02480.0095-0.005-0.0203-0.0144-0.017338.805215.802134.55
40.2405-0.2209-0.294700.05830.15310.0095-0.047-0.06850.0472-0.0092-0.01940.00810.008-0.00030.00870.0141-0.0044-0.0069-0.00810.002434.550116.878250.1416
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|364 - 416}A364 - 416
2X-RAY DIFFRACTION2{A|417 - 523}A417 - 523
3X-RAY DIFFRACTION3{A|524 - 598}A524 - 598
4X-RAY DIFFRACTION4{A|599 - 633}A599 - 633

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