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- PDB-5cxz: SYK catalytic domain complexed with naphthyridine inhibitor -

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Basic information

Entry
Database: PDB / ID: 5cxz
TitleSYK catalytic domain complexed with naphthyridine inhibitor
ComponentsTyrosine-protein kinase SYK
KeywordsTransferase/transferase inhibitor / 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 / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / cellular response to lectin / 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 / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / cellular response to lectin / 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 / positive regulation of mast cell cytokine production / neutrophil activation involved in immune response / positive regulation of mast cell degranulation / cell surface pattern recognition receptor signaling pathway / lymph vessel development / collagen-activated tyrosine kinase 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 / macrophage activation involved in immune response / regulation of phagocytosis / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / cellular response to lipid / regulation of DNA-binding transcription factor activity / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of alpha-beta T cell differentiation / positive regulation of cell adhesion mediated by integrin / 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 / phospholipase binding / amyloid-beta clearance / positive regulation of interleukin-10 production / positive regulation of receptor internalization / FCGR activation / cellular response to low-density lipoprotein particle stimulus / positive regulation of type I interferon production / Role of LAT2/NTAL/LAB on calcium mobilization / Role of phospholipids in phagocytosis / positive regulation of bone resorption / phosphatase binding / regulation of ERK1 and ERK2 cascade / Signaling by CSF3 (G-CSF) / GPVI-mediated activation cascade / positive regulation of TORC1 signaling / positive regulation of interleukin-12 production / phosphotyrosine residue binding / neutrophil chemotaxis / Integrin signaling / FCERI mediated Ca+2 mobilization / positive regulation of calcium-mediated signaling / B cell differentiation / SH2 domain binding / 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 / Regulation of signaling by CBL / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / FCERI mediated MAPK activation / apoptotic signaling pathway / positive regulation of protein-containing complex assembly / non-membrane spanning protein tyrosine kinase activity / negative regulation of inflammatory response to antigenic stimulus / non-specific protein-tyrosine kinase / calcium-mediated signaling / Inactivation of CSF3 (G-CSF) signaling / peptidyl-tyrosine phosphorylation / receptor internalization / Regulation of actin dynamics for phagocytic cup formation / CLEC7A (Dectin-1) signaling / platelet activation / positive regulation of interleukin-6 production / cell surface receptor protein tyrosine kinase signaling pathway / 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 / 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-55U / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsThoma, G. / Veenstra, S. / Strang, R. / Blanz, J. / Vangrevelinghe, E. / Berghausen, J. / Lee, C.C. / Zerwes, H.-G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.
Authors: Thoma, G. / Veenstra, S. / Strang, R. / Blanz, J. / Vangrevelinghe, E. / Berghausen, J. / Lee, C.C. / Zerwes, H.G.
History
DepositionJul 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations / Refinement description
Category: citation / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1194
Polymers33,6701
Non-polymers4493
Water2,486138
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.080, 87.980, 88.500
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 33669.762 Da / Num. of mol.: 1 / Fragment: UNP residues 356-635 / Mutation: K467T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-55U / N-{7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl}propane-1,3-diamine


Mass: 321.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / 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: 2.44 Å3/Da / Density % sol: 49.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 3350 15%, cesium chloride 0.15M

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 27, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 31610 / % possible obs: 90.3 % / Redundancy: 4.5 % / Biso Wilson estimate: 16.6 Å2 / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.039 / Rrim(I) all: 0.085 / Χ2: 0.947 / Net I/av σ(I): 18.552 / Net I/σ(I): 11.6 / Num. measured all: 140709
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.7-1.733.60.59811160.8050.3420.6940.91964.7
1.73-1.763.80.54111100.8250.3010.6230.95565.6
1.76-1.793.80.55312050.8540.3030.6340.97970
1.79-1.833.90.45412790.890.250.5210.96374.4
1.83-1.8740.4613260.9170.2520.5270.92977.5
1.87-1.914.10.36314390.9350.1950.4130.95782
1.91-1.964.10.32214750.9520.1720.3670.9586.5
1.96-2.024.20.25915760.9710.1390.2950.95990.6
2.02-2.074.30.23416360.9730.1230.2651.02495.3
2.07-2.144.50.21917190.9730.1140.2480.89498.3
2.14-2.224.80.17617310.9880.0880.1971.01899.8
2.22-2.314.90.16617260.9880.0830.1860.996100
2.31-2.414.90.13817240.9880.070.1550.99699.9
2.41-2.544.80.11517650.9910.0580.1290.957100
2.54-2.74.80.10817620.9880.0550.1220.937100
2.7-2.914.80.10517540.9890.0530.1181.00299.8
2.91-3.24.80.117490.9850.0510.1121.00699.8
3.2-3.664.70.08317910.990.0430.0930.77899.9
3.66-4.614.60.04718100.9950.0250.0541.07599.9
4.61-504.50.03519170.9960.0190.0410.67699.5

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→20.22 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.9333 / SU R Cruickshank DPI: 0.132 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.136 / SU Rfree Blow DPI: 0.116 / SU Rfree Cruickshank DPI: 0.114
RfactorNum. reflection% reflectionSelection details
Rfree0.208 1265 4.78 %RANDOM
Rwork0.1945 ---
obs0.1952 26464 75.14 %-
Displacement parametersBiso max: 129.43 Å2 / Biso mean: 27.62 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--0.0445 Å20 Å20 Å2
2---3.257 Å20 Å2
3---3.3015 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 1.7→20.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2124 0 31 138 2293
Biso mean--18.38 28.04 -
Num. residues----269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d763SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes315HARMONIC5
X-RAY DIFFRACTIONt_it2210HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion269SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies2HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2608SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2210HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2990HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion17.09
LS refinement shellResolution: 1.7→1.77 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.203 67 5.5 %
Rwork0.2064 1152 -
all0.2062 1219 -
obs--75.14 %
Refinement TLS params.Method: refined / Origin x: 4.2957 Å / Origin y: 10.8337 Å / Origin z: 19.2675 Å
111213212223313233
T-0.1932 Å2-0.0026 Å20.0003 Å2--0.197 Å20.0128 Å2---0.0624 Å2
L2.0446 °2-0.1828 °2-0.7792 °2-5.0816 °2-0.9213 °2--0.8519 °2
S-0.1766 Å °-0.0443 Å °-0.0399 Å °0.0442 Å °0.0412 Å °-0.5377 Å °0.0994 Å °0.0401 Å °0.1355 Å °
Refinement TLS groupSelection details: { A|* }

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