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- PDB-5y5u: Crystal structures of spleen tyrosine kinase in complex with a no... -

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Basic information

Entry
Database: PDB / ID: 5y5u
TitleCrystal structures of spleen tyrosine kinase in complex with a novel inhibitor
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Spleen Tyrosine Kinase / human kinase / drug discovery / TRANSFERASE / 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 / collagen-activated tyrosine kinase receptor signaling pathway / regulation of platelet activation / cell activation / positive regulation of killing of cells of another organism / beta selection / macrophage activation involved in immune response / regulation of phagocytosis / cellular response to molecule of fungal origin / early phagosome / 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 / positive regulation of granulocyte macrophage colony-stimulating factor production / Interleukin-2 signaling / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / positive regulation of B cell differentiation / T cell receptor complex / leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway involved in phagocytosis / mast cell degranulation / Dectin-2 family / positive regulation of interleukin-4 production / : / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / phospholipase binding / amyloid-beta clearance / 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 / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / phosphatase binding / Signaling by CSF3 (G-CSF) / cell surface receptor protein tyrosine kinase signaling pathway / GPVI-mediated activation cascade / positive regulation of interleukin-12 production / neutrophil chemotaxis / positive regulation of TORC1 signaling / phosphotyrosine residue binding / positive regulation of calcium-mediated signaling / Integrin signaling / SH2 domain binding / FCERI mediated Ca+2 mobilization / regulation of ERK1 and ERK2 cascade / B cell differentiation / FCGR3A-mediated IL10 synthesis / 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 / animal organ morphogenesis / FCERI mediated MAPK activation / negative regulation of inflammatory response to antigenic stimulus / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / calcium-mediated signaling / 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 / 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-8OU / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.14 Å
AuthorsLee, S.J. / Lee, B.I.
CitationJournal: Mol. Cells / Year: 2018
Title: Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors.
Authors: Lee, S.J. / Choi, J.S. / Bong, S.M. / Hwang, H.J. / Lee, J. / Song, H.J. / Lee, J. / Kim, J.H. / Koh, J.S. / Lee, B.I.
History
DepositionAug 9, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 27, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 22, 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

Downloads & links

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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)69,2164
Polymers68,4332
Non-polymers7832
Water1,20767
1
A: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6082
Polymers34,2161
Non-polymers3911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6082
Polymers34,2161
Non-polymers3911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.155, 42.013, 87.660
Angle α, β, γ (deg.)79.83, 90.78, 79.60
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: 34216.398 Da / Num. of mol.: 2 / Fragment: UNP 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-8OU / 4-[(1-methylindazol-5-yl)amino]-2-(4-oxidanylpiperidin-1-yl)-8H-pyrido[4,3-d]pyrimidin-5-one / 2-(4-hydroxypiperidin-1-yl)-4-((1-methyl-1H-indazol-5-yl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one


Mass: 391.426 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H21N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 2.09 Å3/Da / Density % sol: 41.14 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 10-20% PEG 3350, 100mM Tris-HCl, pH 8.5

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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: 2.13→30 Å / Num. obs: 28936 / % possible obs: 94.3 % / Redundancy: 2.04 % / Rmerge(I) obs: 0.069 / Net I/σ(I): 16.5
Reflection shellResolution: 2.13→2.17 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.284 / Mean I/σ(I) obs: 2.3 / Num. unique all: 1260 / % possible all: 82.4

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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: 2.14→30 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.917 / SU B: 7.107 / SU ML: 0.179 / Cross valid method: THROUGHOUT / ESU R: 0.349 / ESU R Free: 0.23 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25989 1451 5 %RANDOM
Rwork0.23793 ---
obs0.23903 27485 94.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 40.694 Å2
Baniso -1Baniso -2Baniso -3
1--1.37 Å21.58 Å20.17 Å2
2--2.84 Å2-1.36 Å2
3----1.53 Å2
Refinement stepCycle: 1 / Resolution: 2.14→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4249 0 58 67 4374
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.024409
X-RAY DIFFRACTIONr_bond_other_d0.0040.024223
X-RAY DIFFRACTIONr_angle_refined_deg1.6571.9795942
X-RAY DIFFRACTIONr_angle_other_deg1.0633.0039721
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6895518
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.03424.129201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.18715808
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.1311524
X-RAY DIFFRACTIONr_chiral_restr0.0810.2619
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024889
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021019
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_it1.7463.9272087
X-RAY DIFFRACTIONr_mcbond_other1.7463.9262086
X-RAY DIFFRACTIONr_mcangle_it2.9075.8722600
X-RAY DIFFRACTIONr_mcangle_other2.9065.8732601
X-RAY DIFFRACTIONr_scbond_it1.6874.182322
X-RAY DIFFRACTIONr_scbond_other1.6864.182323
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.8566.1773343
X-RAY DIFFRACTIONr_long_range_B_refined4.84231.3445165
X-RAY DIFFRACTIONr_long_range_B_other4.83331.3485157
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.135→2.19 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 84 -
Rwork0.307 1776 -
obs--81.54 %

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