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

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Basic information

Entry
Database: PDB / ID: 5lma
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 / 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 / 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 / positive regulation of receptor internalization / Fc-epsilon receptor signaling pathway / phospholipase binding / positive regulation of type I interferon production / amyloid-beta clearance / positive regulation of interleukin-10 production / FCGR activation / cellular response to low-density lipoprotein particle stimulus / 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 / GPVI-mediated activation cascade / positive regulation of interleukin-12 production / phosphotyrosine residue binding / neutrophil chemotaxis / positive regulation of TORC1 signaling / Integrin signaling / positive regulation of calcium-mediated signaling / regulation of ERK1 and ERK2 cascade / SH2 domain binding / FCERI mediated Ca+2 mobilization / 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-6ZG / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.43 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 1.2May 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
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)32,7325
Polymers32,1621
Non-polymers5704
Water8,161453
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area640 Å2
ΔGint-1 kcal/mol
Surface area13290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.175, 87.454, 39.851
Angle α, β, γ (deg.)90.000, 99.640, 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: 32161.992 Da / Num. of mol.: 1 / 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-6ZG / ~{N}'-[7-(4-methylphenyl)pyrido[3,4-b]pyrazin-5-yl]butane-1,4-diamine


Mass: 307.393 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21N5
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 453 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.11 Å3/Da / Density % sol: 41.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG3350, Sodium formate.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 3, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.43→43.73 Å / Num. obs: 46803 / % possible obs: 96 % / Redundancy: 3.1 % / Biso Wilson estimate: 15.524 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.032 / Net I/σ(I): 20.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsCC1/2Diffraction-ID% possible all
1.43-1.512.10.1075.70.978185.9
4.52-43.733.20.02839.30.998198.2

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Processing

Software
NameVersionClassification
Aimless0.5.12data scaling
REFMAC5.8.0073refinement
PDB_EXTRACT3.2data extraction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: In-house coordinates

Resolution: 1.43→20 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.958 / SU B: 0.973 / SU ML: 0.039 / SU R Cruickshank DPI: 0.0665 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.067 / ESU R Free: 0.068
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.183 2306 4.9 %RANDOM
Rwork0.1559 ---
obs0.1573 44455 95.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 61.76 Å2 / Biso mean: 18.816 Å2 / Biso min: 8.08 Å2
Baniso -1Baniso -2Baniso -3
1-0.52 Å20 Å20.29 Å2
2---0.43 Å2-0 Å2
3----0.17 Å2
Refinement stepCycle: final / Resolution: 1.43→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2184 0 39 453 2676
Biso mean--22.31 31.81 -
Num. residues----268
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0192393
X-RAY DIFFRACTIONr_bond_other_d0.0010.022271
X-RAY DIFFRACTIONr_angle_refined_deg1.1881.9643237
X-RAY DIFFRACTIONr_angle_other_deg0.73635243
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.2835292
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.25824.685111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.42815438
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4931512
X-RAY DIFFRACTIONr_chiral_restr0.0810.2331
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022731
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02556
X-RAY DIFFRACTIONr_mcbond_it1.323.0221138
X-RAY DIFFRACTIONr_mcbond_other1.3183.0191137
X-RAY DIFFRACTIONr_mcangle_it2.0375.0791440
LS refinement shellResolution: 1.43→1.467 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.187 146 -
Rwork0.188 2742 -
all-2888 -
obs--80.65 %

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