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- PDB-6ssb: syk in complex with compound 30 -

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Basic information

Entry
Database: PDB / ID: 6ssb
Titlesyk in complex with compound 30
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE / SYK Kinase TRANSFERASE INHIBITOR
Function / homology
Function and homology information


interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / lymph vessel development / cellular response to lectin / B cell receptor complex / serotonin secretion by platelet / regulation of platelet aggregation / Toll-like receptor binding ...interleukin-15 receptor binding / regulation of superoxide anion generation / regulation of neutrophil degranulation / regulation of arachidonate secretion / lymph vessel development / cellular response to lectin / B cell receptor complex / serotonin secretion by platelet / regulation of platelet aggregation / Toll-like receptor binding / neutrophil activation involved in immune response / leukocyte activation involved in immune response / positive regulation of toll-like receptor 9 signaling pathway / cell surface pattern recognition receptor signaling pathway / cell activation / regulation of platelet activation / FLT3 signaling through SRC family kinases / blood vessel morphogenesis / regulation of phagocytosis / early phagosome / macrophage activation involved in immune response / cellular response to molecule of fungal origin / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / positive regulation of bone resorption / Fc epsilon receptor (FCERI) signaling / Interleukin-2 signaling / positive regulation of cell adhesion mediated by integrin / regulation of tumor necrosis factor-mediated signaling pathway / cellular response to lipid / positive regulation of cGAS/STING signaling pathway / T cell receptor complex / positive regulation of B cell differentiation / leukocyte cell-cell adhesion / positive regulation of interleukin-4 production / Dectin-2 family / stimulatory C-type lectin receptor signaling pathway / Fc-gamma receptor signaling pathway involved in phagocytosis / Fc-epsilon receptor signaling pathway / amyloid-beta clearance / FCGR activation / positive regulation of interleukin-10 production / positive regulation of receptor internalization / Role of LAT2/NTAL/LAB on calcium mobilization / cellular response to low-density lipoprotein particle stimulus / regulation of ERK1 and ERK2 cascade / Role of phospholipids in phagocytosis / positive regulation of interleukin-12 production / phosphatase binding / GPVI-mediated activation cascade / neutrophil chemotaxis / phospholipase binding / Signaling by CSF3 (G-CSF) / positive regulation of superoxide anion generation / Integrin signaling / positive regulation of type I interferon production / phosphotyrosine residue binding / animal organ morphogenesis / peptidyl-tyrosine phosphorylation / SH2 domain binding / FCERI mediated Ca+2 mobilization / positive regulation of TORC1 signaling / B cell receptor signaling pathway / FCGR3A-mediated IL10 synthesis / apoptotic signaling pathway / integrin-mediated signaling pathway / protein import into nucleus / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of interleukin-8 production / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / negative regulation of inflammatory response to antigenic stimulus / non-membrane spanning protein tyrosine kinase activity / Regulation of signaling by CBL / receptor internalization / platelet activation / positive regulation of protein-containing complex assembly / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / Inactivation of CSF3 (G-CSF) signaling / integrin binding / cellular response to amyloid-beta / CLEC7A (Dectin-1) signaling / kinase activity / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / adaptive immune response / DAP12 signaling / positive regulation of cold-induced thermogenesis / protein tyrosine kinase activity / scaffold protein binding / Potential therapeutics for SARS / defense response to bacterium / protein kinase activity / protein phosphorylation / intracellular signal transduction / innate immune response / signaling receptor binding / protein serine/threonine 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-LUE / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 Å
AuthorsRead, J.A.
CitationJournal: To Be Published
Title: Discovery of a Series of Potent, Selective and Orally Bioavailable SYK Inhibitors
Authors: Read, J.A.
History
DepositionSep 6, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3252
Polymers34,8811
Non-polymers4441
Water3,063170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.100, 85.450, 90.570
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 34880.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Production host: Escherichia coli (E. coli)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-LUE / ~{N}-[4-[5-[(dimethylamino)methyl]-1-methyl-pyrazol-3-yl]pyrimidin-2-yl]-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,5-a]pyridin-7-amine


Mass: 444.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24N10O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.48 Å3/Da / Density % sol: 50.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.4 / Details: 0.1M Na3Cit pH 6.4, 16% PEG3350, 0.2M KH2PO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.08→36.7 Å / Num. obs: 19374 / % possible obs: 97.4 % / Redundancy: 3.1 % / CC1/2: 0.996 / Net I/σ(I): 10.9
Reflection shellResolution: 2.08→2.13 Å / Num. unique obs: 8479 / CC1/2: 0.453

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.08→14.6 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.94 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.193 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.208 / SU Rfree Blow DPI: 0.165 / SU Rfree Cruickshank DPI: 0.16
RfactorNum. reflection% reflectionSelection details
Rfree0.225 1014 5.26 %RANDOM
Rwork0.197 ---
obs0.198 19262 99.8 %-
Displacement parametersBiso max: 136.69 Å2 / Biso mean: 50.22 Å2 / Biso min: 27.66 Å2
Baniso -1Baniso -2Baniso -3
1-0.8927 Å20 Å20 Å2
2--4.4302 Å20 Å2
3----5.3229 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 2.08→14.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2074 0 33 170 2277
Biso mean--45.5 57.07 -
Num. residues----268
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d714SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes43HARMONIC2
X-RAY DIFFRACTIONt_gen_planes312HARMONIC5
X-RAY DIFFRACTIONt_it2158HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion266SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2574SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2158HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg2928HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion17.73
LS refinement shellResolution: 2.08→2.19 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.263 123 4.45 %
Rwork0.216 2640 -
all0.218 2763 -
obs--99.75 %
Refinement TLS params.Method: refined / Origin x: 3.8759 Å / Origin y: 10.7127 Å / Origin z: 20.2856 Å
111213212223313233
T-0.1111 Å20.0023 Å20.0048 Å2--0.0872 Å20.0101 Å2--0.0252 Å2
L1.2474 °20.1655 °2-0.9081 °2-2.2375 °2-0.4814 °2--0.6655 °2
S-0.0205 Å °-0.0503 Å °0.0126 Å °-0.0086 Å °0.0244 Å °-0.0428 Å °0.0421 Å °0.0061 Å °-0.0039 Å °
Refinement TLS groupSelection details: { A|* }

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