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- PDB-6hm7: CRYSTAL STRUCTURE OF SPLEEN TYROSINE KINASE (SYK) IN COMPLEX WITH... -

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Basic information

Entry
Database: PDB / ID: 6hm7
TitleCRYSTAL STRUCTURE OF SPLEEN TYROSINE KINASE (SYK) IN COMPLEX WITH A 2-(PHENOXYMETHYL)PYRIDINE INHIBITOR
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / SK363 / SYK / non-receptor tyrosine kinase / spleen tyrosine kinase
Function / homology
Function and homology information


interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / cellular response to lectin / B cell receptor complex / regulation of platelet aggregation ...interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / positive regulation of interleukin-3 production / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / cellular response to lectin / B cell receptor complex / regulation of platelet aggregation / Toll-like receptor binding / serotonin secretion by platelet / positive regulation of alpha-beta T cell proliferation / leukocyte activation involved in immune response / positive regulation of mast cell cytokine production / neutrophil activation involved in immune response / cell surface pattern recognition receptor signaling pathway / positive regulation of mast cell degranulation / lymph vessel development / collagen-activated tyrosine kinase receptor signaling pathway / regulation of platelet activation / cell activation / beta selection / cellular response to molecule of fungal origin / FLT3 signaling through SRC family kinases / early phagosome / leukotriene biosynthetic process / regulation of phagocytosis / macrophage activation involved in immune response / regulation of tumor necrosis factor-mediated signaling pathway / interleukin-3-mediated signaling pathway / positive regulation of monocyte chemotactic protein-1 production / cellular response to lipid / regulation of DNA-binding transcription factor activity / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of cell adhesion mediated by integrin / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / positive regulation of B cell differentiation / leukocyte cell-cell adhesion / T cell receptor complex / mast cell degranulation / Dectin-2 family / positive regulation of interleukin-4 production / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / Fc-gamma receptor signaling pathway involved in phagocytosis / phospholipase binding / amyloid-beta clearance / positive regulation of interleukin-10 production / positive regulation of receptor internalization / cellular response to low-density lipoprotein particle stimulus / FCGR activation / Role of LAT2/NTAL/LAB on calcium mobilization / positive regulation of type I interferon production / Role of phospholipids in phagocytosis / positive regulation of bone resorption / phosphatase binding / regulation of ERK1 and ERK2 cascade / Signaling by CSF3 (G-CSF) / GPVI-mediated activation cascade / neutrophil chemotaxis / phosphotyrosine residue binding / positive regulation of interleukin-12 production / positive regulation of TORC1 signaling / Integrin signaling / FCERI mediated Ca+2 mobilization / B cell differentiation / SH2 domain binding / FCGR3A-mediated IL10 synthesis / positive regulation of calcium-mediated signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of superoxide anion generation / animal organ morphogenesis / integrin-mediated signaling pathway / positive regulation of interleukin-8 production / non-membrane spanning protein tyrosine kinase activity / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Regulation of signaling by CBL / non-specific protein-tyrosine kinase / positive regulation of protein-containing complex assembly / apoptotic signaling pathway / negative regulation of inflammatory response to antigenic stimulus / calcium-mediated signaling / Inactivation of CSF3 (G-CSF) signaling / peptidyl-tyrosine phosphorylation / receptor internalization / Regulation of actin dynamics for phagocytic cup formation / platelet activation / positive regulation of interleukin-6 production / CLEC7A (Dectin-1) signaling / cellular response to amyloid-beta / protein import into nucleus / positive regulation of tumor necrosis factor production / kinase activity / integrin binding
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
BROMIDE ION / Chem-GDH / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.64 Å
AuthorsSomers, D.O.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease.
Authors: Barker, M.D. / Liddle, J. / Atkinson, F.L. / Wilson, D.M. / Dickson, M.C. / Ramirez-Molina, C. / Lewis, H. / Davis, R.P. / Somers, D.O. / Neu, M. / Jones, E. / Watson, R.
History
DepositionSep 12, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 10, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 17, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
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 20, 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)32,8897
Polymers32,1051
Non-polymers7846
Water5,873326
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area840 Å2
ΔGint0 kcal/mol
Surface area13390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.114, 84.892, 40.361
Angle α, β, γ (deg.)90.000, 100.160, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Tyrosine-protein kinase SYK / Spleen tyrosine kinase / p72-Syk


Mass: 32104.941 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 332 molecules

#2: Chemical ChemComp-GDH / 7-[2-methoxy-6-[(4-methylpyridin-2-yl)methoxy]phenyl]-2,3,4,5-tetrahydro-1~{H}-3-benzazepine


Mass: 374.475 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N2O2
#3: Chemical ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Br
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.16 Å3/Da / Density % sol: 43.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: PEG 3350, bistrispropane, sodium bromide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.64→42.446 Å / Num. obs: 33320 / % possible obs: 99.7 % / Redundancy: 3.7 % / Biso Wilson estimate: 20.9 Å2 / Rpim(I) all: 0.04 / Rrim(I) all: 0.077 / Rsym value: 0.065 / Net I/av σ(I): 5.9 / Net I/σ(I): 11.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.64-1.733.70.4911.448460.2970.5750.49199.9
1.73-1.833.70.3042.345950.1840.3560.30499.9
1.83-1.963.70.1933.643470.1170.2260.19399.9
1.96-2.123.70.1275.439940.0770.1490.12799.9
2.12-2.323.70.097.437080.0550.1060.0999.8
2.32-2.593.70.0817.533530.0490.0950.08199.7
2.59-2.993.60.077.429510.0430.0830.0799.6
2.99-3.673.50.04911.325180.030.0580.04999.5
3.67-5.193.60.0411419320.0250.0480.04199.1
5.19-42.4463.60.041810760.0260.0490.04198.7

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Processing

Software
NameVersionClassification
MOSFLM7.0.6data reduction
SCALA3.3.16data scaling
PDB_EXTRACT3.24data extraction
REFMACphasing
REFMAC5.8.0189refinement
Cootmodel building
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: OTHER IN-HOUSE COORDINATES

Resolution: 1.64→20 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.956 / SU B: 2.688 / SU ML: 0.086 / SU R Cruickshank DPI: 0.0995 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.099 / ESU R Free: 0.1
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2101 1683 5.1 %RANDOM
Rwork0.172 ---
obs0.1739 31597 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 83.27 Å2 / Biso mean: 27.959 Å2 / Biso min: 12.13 Å2
Baniso -1Baniso -2Baniso -3
1-3.23 Å20 Å2-0.43 Å2
2---1.81 Å20 Å2
3----1.19 Å2
Refinement stepCycle: final / Resolution: 1.64→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2175 0 41 326 2542
Biso mean--30.92 40.17 -
Num. residues----268
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192285
X-RAY DIFFRACTIONr_bond_other_d0.0020.022085
X-RAY DIFFRACTIONr_angle_refined_deg1.4061.9833087
X-RAY DIFFRACTIONr_angle_other_deg0.89634838
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4685272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.07924.327104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.07415405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4311512
X-RAY DIFFRACTIONr_chiral_restr0.0850.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022554
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02466
LS refinement shellResolution: 1.64→1.682 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 102 -
Rwork0.284 2357 -
all-2459 -
obs--99.96 %

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