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- PDB-5lmb: HUMAN SPLEEN TYROSINE KINASE KINASE DOMAIN IN COMPLEX WITH AZANAP... -

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Basic information

Entry
Database: PDB / ID: 5lmb
TitleHUMAN SPLEEN TYROSINE KINASE KINASE DOMAIN IN COMPLEX WITH AZANAPHTHYRIDINE INHIBITOR
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / Inhibitor / Complex / Kinase
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 / 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 arachidonate 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 / 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 / Interleukin-2 signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / 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 / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / 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 / Signaling by CSF3 (G-CSF) / cell surface receptor protein tyrosine kinase signaling pathway / negative regulation of inflammatory response to antigenic stimulus / GPVI-mediated activation cascade / positive regulation of TORC1 signaling / positive regulation of interleukin-12 production / positive regulation of calcium-mediated signaling / neutrophil chemotaxis / phosphotyrosine residue binding / Integrin signaling / FCERI mediated Ca+2 mobilization / SH2 domain binding / 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 / FCERI mediated MAPK activation / animal organ morphogenesis / 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 / 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-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-6ZF / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.95 Å
AuthorsSomers, D.O. / Neu, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors.
Authors: Garton, N.S. / Barker, M.D. / Davis, R.P. / Douault, C. / Hooper-Greenhill, E. / Jones, E. / Lewis, H.D. / Liddle, J. / Lugo, D. / McCleary, S. / Preston, A.G. / Ramirez-Molina, C. / Neu, M. ...Authors: Garton, N.S. / Barker, M.D. / Davis, R.P. / Douault, C. / Hooper-Greenhill, E. / Jones, E. / Lewis, H.D. / Liddle, J. / Lugo, D. / McCleary, S. / Preston, A.G. / Ramirez-Molina, C. / Neu, M. / Shipley, T.J. / Somers, D.O. / Watson, R.J. / Wilson, D.M.
History
DepositionJul 29, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 14, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2016Group: Database references
Revision 1.2Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.3May 1, 2024Group: 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)65,69611
Polymers64,3242
Non-polymers1,3729
Water7,098394
1
A: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9867
Polymers32,1621
Non-polymers8246
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7104
Polymers32,1621
Non-polymers5483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.849, 41.780, 86.991
Angle α, β, γ (deg.)99.810, 90.410, 100.030
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: 32161.992 Da / Num. of mol.: 2 / Fragment: UNP residues 360-635
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Plasmid: pFastBac1-HM / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-6ZF / 7-[6-(dimethylamino)pyridin-3-yl]-~{N}-[[(3~{S})-piperidin-3-yl]methyl]pyrido[3,4-b]pyrazin-5-amine


Mass: 363.459 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25N7
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 394 / 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: 2.18 Å3/Da / Density % sol: 43.66 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8 / Details: PEG1500, HEPES, TACSIMATE, GLYCEROL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0724 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 6, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0724 Å / Relative weight: 1
ReflectionResolution: 1.95→42.835 Å / Num. obs: 37810 / % possible obs: 95.3 % / Redundancy: 1.9 % / Biso Wilson estimate: 29.388 Å2 / Rmerge(I) obs: 0.055 / Rsym value: 0.055 / Net I/av σ(I): 8.872 / Net I/σ(I): 8.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.95-2.061.90.41.8192.8
2.06-2.181.90.2632.7193.7
2.18-2.331.90.1734.2194.7
2.33-2.521.90.1226196
2.52-2.761.90.0838.6196.5
2.76-3.081.90.05511.9196.4
3.08-3.561.90.04115.2195.7
3.56-4.361.80.03414.3197.1
4.36-6.171.90.03116.5198.2
6.17-42.8351.90.02918.5194.6

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Processing

Software
NameVersionClassification
SCALA3.3.1data scaling
REFMAC5.8.0073refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: In-house coordinates

Resolution: 1.95→20 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.945 / SU B: 11.086 / SU ML: 0.161 / SU R Cruickshank DPI: 0.1898 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.19 / ESU R Free: 0.168
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2281 1888 5 %RANDOM
Rwork0.1751 ---
obs0.1777 35896 95.21 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 105.54 Å2 / Biso mean: 43.673 Å2 / Biso min: 18.05 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å2-0.94 Å20.04 Å2
2--0.99 Å20.26 Å2
3----0.41 Å2
Refinement stepCycle: final / Resolution: 1.95→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4296 0 96 394 4786
Biso mean--46.51 45.88 -
Num. residues----527
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0194518
X-RAY DIFFRACTIONr_bond_other_d0.0010.024315
X-RAY DIFFRACTIONr_angle_refined_deg1.191.9846084
X-RAY DIFFRACTIONr_angle_other_deg0.76339936
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.0255529
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.88124.195205
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.82315813
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4151524
X-RAY DIFFRACTIONr_chiral_restr0.0780.2631
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025004
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021046
X-RAY DIFFRACTIONr_mcbond_it1.2692.8422119
X-RAY DIFFRACTIONr_mcbond_other1.2672.8412118
X-RAY DIFFRACTIONr_mcangle_it2.0914.7822647
LS refinement shellResolution: 1.95→2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 138 -
Rwork0.313 2574 -
all-2712 -
obs--91.53 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.22060.9584-0.612.3469-0.46185.9086-0.3720.3442-0.1963-0.51060.18730.0840.7694-0.59050.18470.2262-0.13880.00570.36410.01810.051-8.9671-3.8231-32.1871
21.97330.47560.50651.7415-0.14642.9408-0.09530.04350.04340.09130.0359-0.0573-0.1159-0.02750.05940.0146-0.0029-0.00850.14270.02710.00970.79193.2909-10.5979
32.85440.575-1.22043.47370.91577.1833-0.0599-0.15190.0732-0.29030.071-0.1537-0.74250.3029-0.01110.148-0.0130.00390.13620.01550.04313.384525.1149-70.8235
42.73491.3048-2.10952.0909-1.68227.5516-0.3716-0.0408-0.1245-0.1758-0.0366-0.09920.8436-0.31180.40820.1378-0.03580.02180.18450.03990.05683.30910.4689-53.4183
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A364 - 453
2X-RAY DIFFRACTION2A454 - 634
3X-RAY DIFFRACTION3B364 - 453
4X-RAY DIFFRACTION4B454 - 630

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