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- PDB-3emg: Discovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines a... -

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Basic information

Entry
Database: PDB / ID: 3emg
TitleDiscovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines as potent inhibitors of spleen tyrosine kinase (SYK)
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / kinase / syk / Alternative splicing / ATP-binding / Host-virus interaction / Nucleotide-binding / Phosphoprotein / Polymorphism / SH2 domain / Tyrosine-protein kinase / Ubl conjugation
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 / cellular response to lectin / B cell receptor complex / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation ...interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / positive regulation of interleukin-3 production / cellular response to lectin / B cell receptor complex / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation / serotonin secretion by platelet / leukocyte activation involved in immune response / positive regulation of mast cell cytokine production / lymph vessel development / neutrophil activation involved in immune response / positive regulation of mast cell degranulation / gamma-delta T cell differentiation / collagen-activated tyrosine kinase receptor signaling pathway / positive regulation of gamma-delta T cell differentiation / cell surface pattern recognition 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 / regulation of tumor necrosis factor-mediated signaling pathway / regulation of DNA-binding transcription factor activity / macrophage activation involved in immune response / interleukin-3-mediated signaling pathway / positive regulation of monocyte chemotactic protein-1 production / cellular response to lipid / 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 / T cell receptor complex / leukocyte cell-cell adhesion / 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 / amyloid-beta clearance / positive regulation of bone resorption / 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 / phosphatase binding / regulation of ERK1 and ERK2 cascade / phospholipase binding / Signaling by CSF3 (G-CSF) / GPVI-mediated activation cascade / phosphotyrosine residue binding / neutrophil chemotaxis / positive regulation of interleukin-12 production / Integrin signaling / positive regulation of TORC1 signaling / FCERI mediated Ca+2 mobilization / SH2 domain binding / positive regulation of calcium-mediated signaling / B cell differentiation / FCGR3A-mediated IL10 synthesis / 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 / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / non-membrane spanning protein tyrosine kinase activity / Regulation of signaling by CBL / positive regulation of protein-containing complex assembly / non-specific protein-tyrosine kinase / apoptotic signaling pathway / negative regulation of inflammatory response to antigenic stimulus / peptidyl-tyrosine phosphorylation / calcium-mediated signaling / Inactivation of CSF3 (G-CSF) signaling / Regulation of actin dynamics for phagocytic cup formation / receptor internalization / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-685 / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.6 Å
AuthorsTer Haar, E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Discovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines as potent inhibitors of spleen tyrosine kinase (SYK).
Authors: Farmer, L.J. / Bemis, G. / Britt, S.D. / Cochran, J. / Connors, M. / Harrington, E.M. / Hoock, T. / Markland, W. / Nanthakumar, S. / Taslimi, P. / Ter Haar, E. / Wang, J. / Zhaveri, D. / Salituro, F.G.
History
DepositionSep 24, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)34,1062
Polymers33,7091
Non-polymers3971
Water1,49583
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.870, 84.450, 41.440
Angle α, β, γ (deg.)90.00, 99.63, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase SYK / Spleen tyrosine kinase


Mass: 33708.730 Da / Num. of mol.: 1 / Fragment: Kinase domain: Residues 349-635
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Plasmid: pBev10 Topo / Cell (production host): Insect cells / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): high-5
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-685 / 2-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1S)-2-hydroxy-1-methylethyl]-4-methyl-1,3-thiazole-5-carboxamide / 2-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxypropan-2-yl]-4-methyl-1,3-thiazole-5-carboxamide


Mass: 397.494 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N5O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 2.04 Å3/Da / Density % sol: 39.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 10 mg/mL Protein, 15-20% PEG 8000, 100 mM Sodium nitrate, 100 mM HEPES pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 15, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→39.305 Å / Num. all: 28644 / Num. obs: 15406 / % possible obs: 94 % / Redundancy: 1.9 % / Biso Wilson estimate: 22.9 Å2 / Rmerge(I) obs: 0.058 / Rsym value: 0.058 / Net I/σ(I): 4.525
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.135 / Mean I/σ(I) obs: 2.3 / Num. measured all: 4079 / Num. unique all: 2224 / Rsym value: 0.135 / % possible all: 92.9

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Processing

Software
NameVersionClassificationNB
SCALA3.1.11data processing
CNSrefinement
PDB_EXTRACT3.006data extraction
ADSCQuantumdata collection
MOSFLMdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: in-house apo structure of SYK

Resolution: 2.6→39.305 Å / Occupancy max: 1 / Occupancy min: 1 / Isotropic thermal model: anisotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: The Friedel pairs were used in phasing
RfactorNum. reflection% reflectionSelection details
Rfree0.2217 1034 12.3 %random
Rwork0.1996 ---
all0.1996 8365 --
obs0.1996 8365 99.7 %-
Solvent computationBsol: 29.8718 Å2 / ksol: 0.365859 e/Å3
Displacement parametersBiso max: 68.4 Å2 / Biso mean: 24.373 Å2 / Biso min: 0.91 Å2
Baniso -1Baniso -2Baniso -3
1--0.092 Å20 Å2-0.569 Å2
2---0.182 Å20 Å2
3---0.274 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 2.6→39.305 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2081 0 28 83 2192
LS refinement shellResolution: 2.6→2.64 Å /
RfactorNum. reflection
Rfree0.332 26
Rwork0.261 -
obs-411
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2753685.par
X-RAY DIFFRACTION3water_rep.param

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