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- PDB-5tiu: Crystal structure of SYK kinase domain with inhibitor -

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Basic information

Entry
Database: PDB / ID: 5tiu
TitleCrystal structure of SYK kinase domain with inhibitor
ComponentsTyrosine-protein kinase SYK
KeywordsTransferase/Transferase Inhibitor / Carboxamide Spleen Tyrosine Kinase (Syk) / 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 / serotonin secretion by platelet / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / 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 / serotonin secretion by platelet / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / 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 / neutrophil activation involved in immune response / leukocyte activation involved in immune response / positive regulation of mast cell cytokine production / regulation of platelet activation / lymph vessel development / 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 / leukotriene biosynthetic process / FLT3 signaling through SRC family kinases / 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 / positive regulation of granulocyte macrophage colony-stimulating factor production / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / 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 interleukin-10 production / positive regulation of receptor internalization / 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-7CU / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.49 Å
AuthorsEllis, J.M. / Altman, M.D. / Cash, B. / Haidle, A.M. / Kubiak, R.L. / Maddess, M.L. / Yan, Y. / Northrup, A.B.
CitationJournal: ACS Med Chem Lett / Year: 2016
Title: Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.
Authors: Ellis, J.M. / Altman, M.D. / Cash, B. / Haidle, A.M. / Kubiak, R.L. / Maddess, M.L. / Yan, Y. / Northrup, A.B.
History
DepositionOct 3, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 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
Revision 1.2Apr 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)34,1942
Polymers33,8841
Non-polymers3101
Water4,468248
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.770, 85.470, 89.440
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: 33884.004 Da / Num. of mol.: 1 / Fragment: UNP residues 356-635
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Description: GATEWAY (Invitrogen) adapted pcDNA6 AttB HisC vector
Gene: SYK / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): sf9
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-7CU / 5-{[(2S)-2-aminopropyl]amino}-3-(1H-indol-2-yl)pyrazine-2-carboxamide


Mass: 310.354 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H18N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 248 / 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: 2.24 Å3/Da / Density % sol: 45.16 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: 16% PEG3350, 0.1M Tris pH 7.1-7.4 / PH range: 7.1-7.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 24, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.49→42.74 Å / Num. obs: 50257 / % possible obs: 99.23 % / Redundancy: 6.4 % / Biso Wilson estimate: 24.05 Å2 / Rmerge(I) obs: 0.035 / Net I/σ(I): 23.5
Reflection shellResolution: 1.49→1.57 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.463 / Mean I/σ(I) obs: 3.3 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.9.7refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal structure

Resolution: 1.49→21.82 Å / Cor.coef. Fo:Fc: 0.9594 / Cor.coef. Fo:Fc free: 0.9577 / SU R Cruickshank DPI: 0.067 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.071 / SU Rfree Blow DPI: 0.069 / SU Rfree Cruickshank DPI: 0.066
RfactorNum. reflection% reflectionSelection details
Rfree0.2033 2553 5.08 %RANDOM
Rwork0.185 ---
obs0.1859 50257 99.23 %-
Displacement parametersBiso mean: 29.23 Å2
Baniso -1Baniso -2Baniso -3
1-2.0006 Å20 Å20 Å2
2--1.6168 Å20 Å2
3----3.6174 Å2
Refine analyzeLuzzati coordinate error obs: 0.175 Å
Refinement stepCycle: 1 / Resolution: 1.49→21.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2150 0 23 248 2421
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012225HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.013007HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d776SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes325HARMONIC5
X-RAY DIFFRACTIONt_it2225HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.49
X-RAY DIFFRACTIONt_other_torsion16.27
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion267SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2837SEMIHARMONIC4
LS refinement shellResolution: 1.49→1.53 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.237 192 5.67 %
Rwork0.2083 3197 -
all0.2101 3389 -
obs--99.23 %

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