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- PDB-6vov: Crystal structure of Syk in complex with GS-9876 -

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Basic information

Entry
Database: PDB / ID: 6vov
TitleCrystal structure of Syk in complex with GS-9876
ComponentsTyrosine-protein kinase SYK
KeywordsIMMUNE SYSTEM / Spleen tyrosine kinase B-cell Syk
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 / cellular response to lectin / B cell receptor complex / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation ...interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / positive regulation of interleukin-3 production / cellular response to lectin / B cell receptor complex / Toll-like receptor binding / regulation of platelet aggregation / positive regulation of alpha-beta T cell proliferation / serotonin secretion by platelet / leukocyte activation involved in immune response / neutrophil activation involved in immune response / lymph vessel development / positive regulation of mast cell degranulation / gamma-delta T cell differentiation / positive regulation of mast cell cytokine production / collagen-activated tyrosine kinase receptor signaling pathway / positive regulation of gamma-delta T cell differentiation / cell surface pattern recognition receptor signaling pathway / regulation of platelet activation / cell activation / beta selection / cellular response to molecule of fungal origin / FLT3 signaling through SRC family kinases / leukotriene biosynthetic process / early phagosome / regulation of phagocytosis / : / macrophage activation involved in immune response / interleukin-3-mediated signaling pathway / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of bone resorption / positive regulation of monocyte chemotactic protein-1 production / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / cellular response to lipid / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / positive regulation of cell adhesion mediated by integrin / positive regulation of B cell differentiation / leukocyte cell-cell adhesion / mast cell degranulation / T cell receptor complex / Dectin-2 family / positive regulation of interleukin-4 production / Fc-epsilon receptor signaling pathway / stimulatory C-type lectin receptor signaling pathway / Fc-gamma receptor signaling pathway involved in phagocytosis / amyloid-beta clearance / FCGR activation / positive regulation of interleukin-10 production / positive regulation of receptor internalization / cellular response to low-density lipoprotein particle stimulus / Role of LAT2/NTAL/LAB on calcium mobilization / positive regulation of type I interferon production / Role of phospholipids in phagocytosis / phosphatase binding / regulation of ERK1 and ERK2 cascade / GPVI-mediated activation cascade / phospholipase binding / Signaling by CSF3 (G-CSF) / positive regulation of superoxide anion generation / phosphotyrosine residue binding / Integrin signaling / neutrophil chemotaxis / positive regulation of interleukin-12 production / positive regulation of TORC1 signaling / FCERI mediated Ca+2 mobilization / positive regulation of calcium-mediated signaling / FCGR3A-mediated IL10 synthesis / SH2 domain binding / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / peptidyl-tyrosine phosphorylation / B cell differentiation / animal organ morphogenesis / integrin-mediated signaling pathway / B cell receptor signaling pathway / positive regulation of interleukin-8 production / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / non-specific protein-tyrosine kinase / Regulation of signaling by CBL / apoptotic signaling pathway / negative regulation of inflammatory response to antigenic stimulus / positive regulation of protein-containing complex assembly / calcium-mediated signaling / Inactivation of CSF3 (G-CSF) signaling / platelet activation / Regulation of actin dynamics for phagocytic cup formation / receptor internalization / positive regulation of interleukin-6 production / CLEC7A (Dectin-1) signaling / integrin binding / cellular response to amyloid-beta / protein import into nucleus / positive regulation of tumor necrosis factor production / kinase activity
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
Chem-R6D / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsLansdon, E.B.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases.
Authors: Blomgren, P. / Chandrasekhar, J. / Di Paolo, J.A. / Fung, W. / Geng, G. / Ip, C. / Jones, R. / Kropf, J.E. / Lansdon, E.B. / Lee, S. / Lo, J.R. / Mitchell, S.A. / Murray, B. / Pohlmeyer, C. ...Authors: Blomgren, P. / Chandrasekhar, J. / Di Paolo, J.A. / Fung, W. / Geng, G. / Ip, C. / Jones, R. / Kropf, J.E. / Lansdon, E.B. / Lee, S. / Lo, J.R. / Mitchell, S.A. / Murray, B. / Pohlmeyer, C. / Schmitt, A. / Suekawa-Pirrone, K. / Wise, S. / Xiong, J.M. / Xu, J. / Yu, H. / Zhao, Z. / Currie, K.S.
History
DepositionJan 31, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 11, 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

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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)66,2564
Polymers65,3692
Non-polymers8872
Water3,189177
1
A: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1282
Polymers32,6851
Non-polymers4441
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase SYK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1282
Polymers32,6851
Non-polymers4441
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.973, 42.050, 87.613
Angle α, β, γ (deg.)81.015, 90.330, 79.252
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

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


Mass: 32684.592 Da / Num. of mol.: 2 / Fragment: UNP Residues 363-635
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-R6D / 6-(6-aminopyrazin-2-yl)-N-{4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}imidazo[1,2-a]pyrazin-8-amine / GS-9876


Mass: 443.504 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C23H25N9O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 177 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 43.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 20% PEG 3350, 100mM Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 85949 / % possible obs: 94.6 % / Redundancy: 2.3 % / Biso Wilson estimate: 18.89 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 13.8
Reflection shellResolution: 1.95→1.99 Å / Num. unique obs: 1851 / Rrim(I) all: 0.479

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1XBA

1xba


Resolution: 1.95→35.26 Å / SU ML: 0.2653 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 29.6848
RfactorNum. reflection% reflection
Rfree0.2675 2000 6.33 %
Rwork0.2171 --
obs0.2202 31599 78.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 25.32 Å2
Refinement stepCycle: LAST / Resolution: 1.95→35.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4245 0 66 177 4488
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00914416
X-RAY DIFFRACTIONf_angle_d1.30925952
X-RAY DIFFRACTIONf_chiral_restr0.0838616
X-RAY DIFFRACTIONf_plane_restr0.01741
X-RAY DIFFRACTIONf_dihedral_angle_d15.4681679
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-20.3292820.22861223X-RAY DIFFRACTION44.42
2-2.050.3633940.24831393X-RAY DIFFRACTION52.51
2.05-2.110.35821000.25941482X-RAY DIFFRACTION53.77
2.11-2.180.31311110.24161637X-RAY DIFFRACTION60.61
2.18-2.260.32141170.24321729X-RAY DIFFRACTION64.48
2.26-2.350.32141310.2421939X-RAY DIFFRACTION70.99
2.35-2.450.30321470.24552177X-RAY DIFFRACTION80.75
2.45-2.580.27421590.24542340X-RAY DIFFRACTION87.65
2.58-2.750.31551730.24662576X-RAY DIFFRACTION94.7
2.75-2.960.2821780.25212622X-RAY DIFFRACTION96.99
2.96-3.250.28921780.23152638X-RAY DIFFRACTION97.04
3.26-3.730.25361770.20472617X-RAY DIFFRACTION96.38
3.73-4.690.20281760.1742613X-RAY DIFFRACTION96.81
4.69-35.260.2221770.18522613X-RAY DIFFRACTION96.54

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