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- PDB-4px6: SYK catalytic domain in complex with a potent pyridopyrimidinone ... -

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Basic information

Entry
Database: PDB / ID: 4px6
TitleSYK catalytic domain in complex with a potent pyridopyrimidinone inhibitor
ComponentsTyrosine-protein kinase SYK
Keywordstransferase/transferase inhibitor / kinase domain / phosphotransferase / 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-2X6 / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsLee, C.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Syk inhibitors with high potency in presence of blood.
Authors: Thoma, G. / Blanz, J. / Buhlmayer, P. / Druckes, P. / Kittelmann, M. / Smith, A.B. / van Eis, M. / Vangrevelinghe, E. / Zerwes, H.G. / Che, J.J. / He, X. / Jin, Y. / Lee, C.C. / Michellys, P. ...Authors: Thoma, G. / Blanz, J. / Buhlmayer, P. / Druckes, P. / Kittelmann, M. / Smith, A.B. / van Eis, M. / Vangrevelinghe, E. / Zerwes, H.G. / Che, J.J. / He, X. / Jin, Y. / Lee, C.C. / Michellys, P.Y. / Uno, T. / Liu, H.
History
DepositionMar 21, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 23, 2014Provider: repository / Type: Initial release
Revision 1.1May 21, 2014Group: Database references
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)34,2452
Polymers33,8561
Non-polymers3891
Water4,504250
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.889, 85.161, 88.961
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: 33855.930 Da / Num. of mol.: 1 / Fragment: Catalytic Domain / Mutation: K467T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-2X6 / 7-{[(1R,2S)-2-aminocyclohexyl]amino}-5-(1H-indol-7-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one


Mass: 389.454 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23N7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 250 / 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: 2.23 Å3/Da / Density % sol: 44.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.2
Details: 20% PEG3350, 0.2M ammonium fluoride, pH 6.2, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 8-BM / Wavelength: 1
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→85.16 Å / Num. all: 39941 / Num. obs: 240351 / % possible obs: 93.1 % / Biso Wilson estimate: 24.36 Å2 / Rmerge(I) obs: 0.035 / Rsym value: 0.042 / Net I/σ(I): 24.4
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.397 / Mean I/σ(I) obs: 2.2 / Rsym value: 0.539 / % possible all: 85.3

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Processing

Software
NameVersionClassification
REFMACrefinement
BUSTER2.11.2refinement
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1XBA

1xba


Resolution: 1.6→23.37 Å / Cor.coef. Fo:Fc: 0.9574 / Cor.coef. Fo:Fc free: 0.9437 / SU R Cruickshank DPI: 0.079 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.202 1991 5 %RANDOM
Rwork0.1748 ---
obs0.1761 39834 97.7 %-
all-40771 --
Displacement parametersBiso mean: 29.35 Å2
Baniso -1Baniso -2Baniso -3
1-1.8322 Å20 Å20 Å2
2--2.0994 Å20 Å2
3----3.9316 Å2
Refine analyzeLuzzati coordinate error obs: 0.191 Å
Refinement stepCycle: LAST / Resolution: 1.6→23.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2087 0 29 250 2366
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012178HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.952947HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d755SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes342HARMONIC5
X-RAY DIFFRACTIONt_it2178HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.39
X-RAY DIFFRACTIONt_other_torsion16.09
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion265SEMIHARMONIC5
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_contact2834SEMIHARMONIC4
LS refinement shellResolution: 1.6→1.64 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2178 113 4.84 %
Rwork0.2134 2221 -
all0.2136 2334 -
obs--97.7 %
Refinement TLS params.Method: refined / Origin x: 3.7251 Å / Origin y: 11.0332 Å / Origin z: 19.5229 Å
111213212223313233
T-0.0449 Å2-0.0113 Å20.0105 Å2--0.0543 Å20.0032 Å2---0.0613 Å2
L1.5326 °2-0.6807 °2-0.4528 °2-1.4283 °2-0.0245 °2--0.5961 °2
S-0.0232 Å °-0.0928 Å °0.038 Å °-0.0034 Å °0.0319 Å °0.0246 Å °0.0427 Å °0.043 Å °-0.0088 Å °
Refinement TLS groupSelection details: { A|* }

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