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- PDB-4pv0: Crystal structure of spleen tyrosine kinase (Syk) in complex with... -

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Basic information

Entry
Database: PDB / ID: 4pv0
TitleCrystal structure of spleen tyrosine kinase (Syk) in complex with an imidazopyrazine inhibitor
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Syk / spleen tyrosine kinase / kinase inhibitor / protein kinase / 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-CG4 / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2 Å
AuthorsLansdon, E.B. / Mitchell, S.A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase.
Authors: Currie, K.S. / Kropf, J.E. / Lee, T. / Blomgren, P. / Xu, J. / Zhao, Z. / Gallion, S. / Whitney, J.A. / Maclin, D. / Lansdon, E.B. / Maciejewski, P. / Rossi, A.M. / Rong, H. / Macaluso, J. / ...Authors: Currie, K.S. / Kropf, J.E. / Lee, T. / Blomgren, P. / Xu, J. / Zhao, Z. / Gallion, S. / Whitney, J.A. / Maclin, D. / Lansdon, E.B. / Maciejewski, P. / Rossi, A.M. / Rong, H. / Macaluso, J. / Barbosa, J. / Di Paolo, J.A. / Mitchell, S.A.
History
DepositionMar 14, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 21, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

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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)32,5437
Polymers31,8561
Non-polymers6876
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.788, 84.972, 90.308
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Tyrosine-protein kinase SYK / Spleen tyrosine kinase / p72-Syk


Mass: 31855.723 Da / Num. of mol.: 1 / Fragment: Syk kinase domain, UNP residues 363-635
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-CG4 / 4-[(3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzoyl)amino]benzoic acid


Mass: 509.513 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H23N5O5
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 2.47 Å3/Da / Density % sol: 50.18 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / Details: VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationMonochromator: double crystal fixed exit / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 2→42.49 Å / Num. obs: 20675 / % possible obs: 96.7 % / Observed criterion σ(I): 0 / Redundancy: 4.8 % / Rmerge(I) obs: 0.054
Reflection shellResolution: 2→2.05 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.581 / % possible all: 97.8

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Processing

Software
NameVersionClassification
PHENIX1.7_650refinement
PHASERphasing
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
HKL-2000data collection
RefinementMethod to determine structure: OTHER
Starting model: PDB ENTRY 1XBA

1xba


Resolution: 2→42.486 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.927 / SU ML: 0.28 / σ(F): 1.37 / Phase error: 28.14 / Stereochemistry target values: ML / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rfree0.282 1055 5.1 %
Rwork0.228 --
obs0.2306 20674 96.72 %
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 56.06 Å2 / ksol: 0.348 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.2201 Å2-0 Å20 Å2
2---9.2322 Å2-0 Å2
3---11.4523 Å2
Refinement stepCycle: LAST / Resolution: 2→42.486 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2182 0 43 71 2296
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122273
X-RAY DIFFRACTIONf_angle_d1.2653063
X-RAY DIFFRACTIONf_dihedral_angle_d14.663858
X-RAY DIFFRACTIONf_chiral_restr0.078316
X-RAY DIFFRACTIONf_plane_restr0.005383
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0001-2.09110.37861310.30922436X-RAY DIFFRACTION98
2.0911-2.20130.31941320.27142458X-RAY DIFFRACTION98
2.2013-2.33930.32861320.27432462X-RAY DIFFRACTION98
2.3393-2.51990.30451300.24482410X-RAY DIFFRACTION97
2.5199-2.77340.28971320.23962466X-RAY DIFFRACTION98
2.7734-3.17460.27381330.23612458X-RAY DIFFRACTION97
3.1746-3.99920.25311310.20822437X-RAY DIFFRACTION95
3.9992-42.49560.27281340.20692492X-RAY DIFFRACTION92

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