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- PDB-5cy3: SYK catalytic domain complexed with a potent and orally bioavaila... -

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Basic information

Entry
Database: PDB / ID: 5cy3
TitleSYK catalytic domain complexed with a potent and orally bioavailable benzisothiazole 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 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 / positive regulation of mast cell degranulation / lymph vessel development / regulation of platelet activation / collagen-activated tyrosine kinase receptor signaling pathway / cell activation / 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 / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / cellular response to lipid / 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 / positive regulation of bone resorption / phosphatase binding / 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 / FCERI mediated Ca+2 mobilization / SH2 domain binding / neutrophil chemotaxis / B cell differentiation / FCGR3A-mediated IL10 synthesis / 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 / animal organ morphogenesis / FCGR3A-mediated phagocytosis / 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 peptidyl-tyrosine phosphorylation / positive regulation of tumor necrosis factor production / 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-55Y / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.76 Å
AuthorsLee, C.C.
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 30, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2015Group: Database references
Revision 1.2Dec 16, 2015Group: Refinement description
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)34,2002
Polymers33,8561
Non-polymers3441
Water3,477193
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.504, 37.656, 90.888
Angle α, β, γ (deg.)90.000, 100.140, 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: 33855.930 Da / Num. of mol.: 1 / Fragment: 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-55Y / (5R)-5-[(1R)-1-{[6-(1-methyl-1H-pyrazol-4-yl)-2,1-benzothiazol-4-yl]oxy}ethyl]-1,3-oxazolidin-2-one


Mass: 344.388 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N4O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / 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: 2.17 Å3/Da / Density % sol: 43.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.1 / Details: PEG 3350 20%, ammonium acetate 0.2M

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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: Apr 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 27534 / % possible obs: 98.9 % / Redundancy: 2.6 % / Biso Wilson estimate: 21.27 Å2 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.031 / Rrim(I) all: 0.052 / Χ2: 0.932 / Net I/av σ(I): 22.387 / Net I/σ(I): 12.4 / Num. measured all: 72734
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.75-1.792.50.41418110.80.3150.5230.95198.3
1.79-1.842.70.31317890.8770.2290.390.95798.1
1.84-1.892.70.25218190.9110.1850.314198.3
1.89-1.942.70.19517670.9480.1450.2441.02498.4
1.94-22.70.15118410.9650.110.1871.0198.8
2-2.072.60.11318490.9740.0840.1411.01599.1
2.07-2.162.70.08918110.9860.0650.1110.96199
2.16-2.262.70.07218230.9890.0530.090.92899.2
2.26-2.382.70.06118400.9920.0450.0760.86399.4
2.38-2.522.60.0518490.9920.0370.0630.98199.6
2.52-2.722.70.0418440.9950.0290.050.84799.9
2.72-2.992.60.03618520.9960.0270.0460.89499.7
2.99-3.432.60.03718850.9960.0270.0460.90199.6
3.43-4.322.60.03318500.9960.0250.0420.87699
4.32-502.60.02619040.9970.020.0330.78697.4

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
BUSTER-TNT2.11.5refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.76→39.91 Å / Cor.coef. Fo:Fc: 0.9559 / Cor.coef. Fo:Fc free: 0.947 / SU R Cruickshank DPI: 0.113 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.117 / SU Rfree Blow DPI: 0.105 / SU Rfree Cruickshank DPI: 0.104
RfactorNum. reflection% reflectionSelection details
Rfree0.1947 1319 4.93 %RANDOM
Rwork0.1699 ---
obs0.1711 26766 96.32 %-
Displacement parametersBiso max: 119.61 Å2 / Biso mean: 26.13 Å2 / Biso min: 8.1 Å2
Baniso -1Baniso -2Baniso -3
1--1.1176 Å20 Å20.6773 Å2
2--1.5699 Å20 Å2
3----0.4523 Å2
Refine analyzeLuzzati coordinate error obs: 0.193 Å
Refinement stepCycle: final / Resolution: 1.76→39.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2185 0 24 193 2402
Biso mean--16.36 34.28 -
Num. residues----276
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d784SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes54HARMONIC2
X-RAY DIFFRACTIONt_gen_planes348HARMONIC5
X-RAY DIFFRACTIONt_it2277HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion276SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies3HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2689SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2277HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3085HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion15.49
LS refinement shellResolution: 1.76→1.83 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2273 106 4.41 %
Rwork0.194 2296 -
all0.1954 2402 -
obs--96.32 %
Refinement TLS params.Method: refined / Details: Chain A catalytic domain / Origin x: 1.2456 Å / Origin y: -7.6394 Å / Origin z: -24.0533 Å
111213212223313233
T-0.0836 Å20.0073 Å20.0005 Å2--0.0699 Å20.0131 Å2---0.0661 Å2
L1.347 °20.2662 °20.1474 °2-0.926 °20.1102 °2--1.5144 °2
S0.063 Å °-0.0162 Å °-0.0228 Å °0.1368 Å °-0.0493 Å °0.0234 Å °-0.0276 Å °-0.1562 Å °-0.0137 Å °
Refinement TLS groupSelection details: { A|360 - A|637 }

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