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- PDB-4wnm: SYK catalytic domain in complex with a potent triazolopyridine in... -

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Basic information

Entry
Database: PDB / ID: 4wnm
TitleSYK catalytic domain in complex with a potent triazolopyridine inhibitor
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / SYK catalytic domain in complex with a potent triazolopyridine based inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / cell surface pattern recognition receptor signaling pathway / regulation of platelet activation / cell activation / FLT3 signaling through SRC family kinases / blood vessel morphogenesis / early phagosome / regulation of phagocytosis / macrophage activation involved in immune response / positive regulation of monocyte chemotactic protein-1 production / cellular response to molecule of fungal origin / 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 B cell differentiation / T cell receptor complex / 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 / Signaling by CSF3 (G-CSF) / phospholipase binding / positive regulation of superoxide anion generation / Integrin signaling / phosphotyrosine residue binding / positive regulation of type I interferon production / animal organ morphogenesis / positive regulation of TORC1 signaling / peptidyl-tyrosine phosphorylation / FCERI mediated Ca+2 mobilization / B cell receptor signaling pathway / FCGR3A-mediated IL10 synthesis / SH2 domain binding / integrin-mediated signaling pathway / apoptotic signaling pathway / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / protein import into nucleus / 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 / CLEC7A (Dectin-1) signaling / cellular response to amyloid-beta / kinase activity / positive regulation of tumor necrosis factor production / DAP12 signaling / positive regulation of cold-induced thermogenesis / angiogenesis / protein tyrosine kinase activity / scaffold protein binding / Potential therapeutics for SARS / adaptive immune response / protein kinase activity / protein phosphorylation / defense response to bacterium / intracellular signal transduction / signaling receptor binding / innate immune response / protein serine/threonine kinase activity / regulation of transcription by RNA polymerase II / protein kinase 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-3RT / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.5 Å
AuthorsJackson, P.J.
CitationJournal: Plos One / Year: 2016
Title: A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.
Authors: Ferguson, G.D. / Delgado, M. / Plantevin-Krenitsky, V. / Jensen-Pergakes, K. / Bates, R.J. / Torres, S. / Celeridad, M. / Brown, H. / Burnett, K. / Nadolny, L. / Tehrani, L. / Packard, G. / ...Authors: Ferguson, G.D. / Delgado, M. / Plantevin-Krenitsky, V. / Jensen-Pergakes, K. / Bates, R.J. / Torres, S. / Celeridad, M. / Brown, H. / Burnett, K. / Nadolny, L. / Tehrani, L. / Packard, G. / Pagarigan, B. / Haelewyn, J. / Nguyen, T. / Xu, L. / Tang, Y. / Hickman, M. / Baculi, F. / Pierce, S. / Miyazawa, K. / Jackson, P. / Chamberlain, P. / LeBrun, L. / Xie, W. / Bennett, B. / Blease, K.
History
DepositionOct 13, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)35,4253
Polymers34,8811
Non-polymers5442
Water28816
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-15 kcal/mol
Surface area12920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.871, 84.820, 90.627
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: Spodoptera frugiperda (fall armyworm)
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-3RT / N~3~-(tetrahydro-2H-pyran-4-yl)-N~6~-[5-(tetrahydro-2H-pyran-4-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1H-indazole-3,6-diamine


Mass: 447.533 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29N7O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / 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: 2.2 Å3/Da / Density % sol: 44.01 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop
Details: 100 mM MES pH 5.3, 150 mM Ammonium sulfate, and 22% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 22, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 9994 / % possible obs: 88.9 % / Redundancy: 2.4 % / Rmerge(I) obs: 0.082 / Χ2: 2.159 / Net I/av σ(I): 16.014 / Net I/σ(I): 11.2 / Num. measured all: 24433
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.5-2.542.40.764881.23888.6
2.54-2.592.40.5324881.22889.9
2.59-2.642.40.4514991.15591.2
2.64-2.692.40.4144961.27490.7
2.69-2.752.40.3074861.42389.7
2.75-2.822.40.2975101.46991.7
2.82-2.892.50.2524991.46191.6
2.89-2.962.40.2184991.54890.2
2.96-3.052.40.1795131.8691.4
3.05-3.152.50.145002.05990.7
3.15-3.262.40.1275142.12691.5
3.26-3.392.40.1094902.38490.4
3.39-3.552.50.15202.66891.1
3.55-3.732.40.0774933.11689
3.73-3.972.40.0695103.03189
3.97-4.272.40.0574882.64887.5
4.27-4.72.40.0534963.24986.6
4.7-5.382.50.0534882.99585
5.38-6.782.60.0545072.81184.9
6.78-502.50.0425103.12778.8

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Processing

Software
NameVersionClassification
HKL-2000data reduction
REFMAC5.8.0049refinement
PDB_EXTRACT3.15data extraction
RefinementResolution: 2.5→50 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.918 / SU B: 13.091 / SU ML: 0.272 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.041 / ESU R Free: 0.332 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.26 475 4.8 %RANDOM
Rwork0.2039 9503 --
obs0.2067 9503 88.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 116.85 Å2 / Biso mean: 48.453 Å2 / Biso min: 24.17 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å2-0 Å2
2---0.01 Å20 Å2
3---0.03 Å2
Refinement stepCycle: final / Resolution: 2.5→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2172 0 38 16 2226
Biso mean--47.59 38.74 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.022265
X-RAY DIFFRACTIONr_bond_other_d0.0010.022105
X-RAY DIFFRACTIONr_angle_refined_deg1.5171.943066
X-RAY DIFFRACTIONr_angle_other_deg0.81934787
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8925270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.54223.981103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.49415378
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.0631512
X-RAY DIFFRACTIONr_chiral_restr0.0850.2324
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022543
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02530
X-RAY DIFFRACTIONr_mcbond_it3.2854.721088
X-RAY DIFFRACTIONr_mcbond_other3.2814.721088
X-RAY DIFFRACTIONr_mcangle_it5.0217.0641355
LS refinement shellResolution: 2.496→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.401 37 -
Rwork0.326 653 -
all-690 -
obs--87.01 %

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