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- PDB-4xg9: Crystal structure of an inhibitor-bound Syk -

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Basic information

Entry
Database: PDB / ID: 4xg9
TitleCrystal structure of an inhibitor-bound Syk
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Syk kinase / Inhibitor / Spleen tyrosine 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 arachidonate secretion / cellular response to lectin / positive regulation of interleukin-3 production / 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 / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / cellular response to lectin / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / B cell receptor complex / serotonin secretion by platelet / 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 / positive regulation of mast cell degranulation / lymph vessel development / regulation of platelet activation / collagen-activated tyrosine kinase receptor signaling pathway / cell activation / regulation of phagocytosis / FLT3 signaling through SRC family kinases / cellular response to lipid / positive regulation of killing of cells of another organism / beta selection / macrophage activation involved in immune response / cellular response to molecule of fungal origin / early phagosome / leukotriene biosynthetic process / regulation of DNA-binding transcription factor activity / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / positive regulation of cell adhesion mediated by integrin / positive regulation of granulocyte macrophage colony-stimulating factor production / Interleukin-2 signaling / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / Fc epsilon receptor (FCERI) signaling / Fc-gamma receptor signaling pathway involved in phagocytosis / positive regulation of B cell differentiation / T cell receptor complex / leukocyte cell-cell adhesion / mast cell degranulation / : / positive regulation of interleukin-4 production / Dectin-2 family / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / positive regulation of receptor internalization / phospholipase binding / positive regulation of type I interferon production / amyloid-beta clearance / positive regulation of interleukin-10 production / cellular response to low-density lipoprotein particle stimulus / FCGR activation / positive regulation of bone resorption / phosphatase binding / Role of LAT2/NTAL/LAB on calcium mobilization / Role of phospholipids in phagocytosis / Signaling by CSF3 (G-CSF) / cell surface receptor protein tyrosine kinase signaling pathway / GPVI-mediated activation cascade / positive regulation of interleukin-12 production / phosphotyrosine residue binding / neutrophil chemotaxis / positive regulation of TORC1 signaling / positive regulation of calcium-mediated signaling / Integrin signaling / regulation of ERK1 and ERK2 cascade / FCERI mediated Ca+2 mobilization / SH2 domain binding / FCGR3A-mediated IL10 synthesis / B cell differentiation / 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 / animal organ morphogenesis / negative regulation of inflammatory response to antigenic stimulus / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / calcium-mediated signaling / 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 / positive regulation of interleukin-6 production / protein import into nucleus / cellular response to amyloid-beta / positive regulation of peptidyl-tyrosine phosphorylation / 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-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 / 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-X9G / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.91 Å
AuthorsLee, S.J. / Choi, J. / Han, B.G. / Song, H. / Koh, J.S. / Lee, B.I.
CitationJournal: Febs J. / Year: 2016
Title: Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs
Authors: Lee, S.J. / Choi, J.S. / Han, B.G. / Kim, H.S. / Song, H.J. / Lee, J. / Nam, S. / Goh, S.H. / Kim, J.H. / Koh, J.S. / Lee, B.I.
History
DepositionDec 30, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 30, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2016Group: Database references
Revision 1.2Oct 19, 2016Group: Database references
Revision 1.3Feb 5, 2020Group: Data collection / Derived calculations / Category: diffrn_source / pdbx_struct_oper_list
Item: _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Nov 8, 2023Group: 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

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Assembly

Deposited unit
A: Tyrosine-protein kinase SYK
B: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6784
Polymers67,8022
Non-polymers8762
Water543
1
A: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3392
Polymers33,9011
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3392
Polymers33,9011
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.068, 42.094, 87.899
Angle α, β, γ (deg.)99.90, 90.42, 100.66
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 33900.965 Da / Num. of mol.: 2 / Fragment: protein kinase domain, residues 356-635
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-X9G / 1-[(1-{2-[(3-chloro-1,2-dimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-3-methyl-1H-pyrazol-4-yl)methyl]azetidin-3-ol


Mass: 437.925 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24ClN7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.12 Å3/Da / Density % sol: 41.85 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 10~20%(v/v) PEG3350, 100 mM Tris-HCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B1 / Wavelength: 1 Å
DetectorType: RIGAKU JUPITER 210 / Detector: CCD / Date: Nov 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 11885 / % possible obs: 98.6 % / Redundancy: 3.6 % / Net I/σ(I): 11.16
Reflection shellResolution: 2.9→2.95 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XG2

4xg2


Resolution: 2.91→50 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.914 / SU B: 18.977 / SU ML: 0.35 / Cross valid method: THROUGHOUT / ESU R Free: 0.451 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24104 554 4.7 %RANDOM
Rwork0.2085 ---
obs0.21008 11331 97.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 49.781 Å2
Baniso -1Baniso -2Baniso -3
1--1.42 Å2-1.16 Å2-0.21 Å2
2--3.66 Å20.85 Å2
3----2.22 Å2
Refinement stepCycle: 1 / Resolution: 2.91→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4260 0 62 3 4325
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.024566
X-RAY DIFFRACTIONr_bond_other_d0.0030.024354
X-RAY DIFFRACTIONr_angle_refined_deg1.3281.9816164
X-RAY DIFFRACTIONr_angle_other_deg1.0673.00510016
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3835538
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.54924.393214
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.6615828
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0311524
X-RAY DIFFRACTIONr_chiral_restr0.0760.2644
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025100
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021054
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.9614.9422164
X-RAY DIFFRACTIONr_mcbond_other1.9574.9382163
X-RAY DIFFRACTIONr_mcangle_it3.4967.3952698
X-RAY DIFFRACTIONr_mcangle_other3.4957.3992699
X-RAY DIFFRACTIONr_scbond_it1.3725.0652402
X-RAY DIFFRACTIONr_scbond_other1.3725.0652403
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.5337.5513463
X-RAY DIFFRACTIONr_long_range_B_refined4.67138.1065112
X-RAY DIFFRACTIONr_long_range_B_other4.67138.1075113
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.911→2.987 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 32 -
Rwork0.29 732 -
obs--83.59 %

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