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- PDB-6zcs: SYK Kinase domain in complex with azabenzimidazole inhibitor 3 -

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Basic information

Entry
Database: PDB / ID: 6zcs
TitleSYK Kinase domain in complex with azabenzimidazole inhibitor 3
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 / 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 / positive regulation of killing of cells of another organism / beta selection / macrophage activation involved in immune response / regulation of phagocytosis / cellular response to molecule of fungal origin / early phagosome / FLT3 signaling through SRC family kinases / leukotriene biosynthetic process / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of monocyte chemotactic protein-1 production / interleukin-3-mediated signaling pathway / cellular response to lipid / regulation of DNA-binding transcription factor activity / positive regulation of cell adhesion mediated by integrin / Fc epsilon receptor (FCERI) signaling / positive regulation of granulocyte macrophage colony-stimulating factor production / Interleukin-2 signaling / positive regulation of alpha-beta T cell differentiation / blood vessel morphogenesis / positive regulation of B cell differentiation / T cell receptor complex / leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway involved in phagocytosis / mast cell degranulation / Dectin-2 family / positive regulation of interleukin-4 production / : / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / phospholipase binding / amyloid-beta clearance / positive regulation of receptor internalization / positive regulation of interleukin-10 production / cellular response to low-density lipoprotein particle stimulus / FCGR activation / positive regulation of type I interferon production / positive regulation of bone resorption / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / phosphatase binding / Signaling by CSF3 (G-CSF) / cell surface receptor protein tyrosine kinase signaling pathway / GPVI-mediated activation cascade / positive regulation of interleukin-12 production / neutrophil chemotaxis / positive regulation of TORC1 signaling / phosphotyrosine residue binding / positive regulation of calcium-mediated signaling / Integrin signaling / SH2 domain binding / FCERI mediated Ca+2 mobilization / regulation of ERK1 and ERK2 cascade / B cell differentiation / FCGR3A-mediated IL10 synthesis / positive regulation of superoxide anion generation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of interleukin-8 production / integrin-mediated signaling pathway / Regulation of signaling by CBL / animal organ morphogenesis / FCERI mediated MAPK activation / negative regulation of inflammatory response to antigenic stimulus / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / calcium-mediated signaling / non-membrane spanning protein tyrosine kinase activity / 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 / 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-QFE / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.47 Å
AuthorsRead, J.A.
CitationJournal: To Be Published
Title: SYK Kinase domain in complex with azabenzimidazole inhibitor 3
Authors: Read, J.A.
History
DepositionJun 12, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 24, 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

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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)35,3092
Polymers34,8811
Non-polymers4281
Water6,305350
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.390, 86.119, 90.901
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-QFE / (3~{R},4~{R})-~{N}4-[1-[2-(1-methylindol-4-yl)-3~{H}-imidazo[4,5-b]pyridin-7-yl]pyrazol-4-yl]oxane-3,4-diamine


Mass: 428.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 350 / 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: 2.27 Å3/Da / Density % sol: 45.72 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / 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: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.47→62.52 Å / Num. obs: 49621 / % possible obs: 90.7 % / Redundancy: 5.3 % / Biso Wilson estimate: 22.08 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.017 / Rrim(I) all: 0.041 / Net I/σ(I): 17.3
Reflection shellResolution: 1.47→1.51 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.81 / Num. unique obs: 2135 / CC1/2: 0.6 / Rpim(I) all: 0.528 / Rrim(I) all: 0.973 / % possible all: 53.7

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Processing

Software
NameVersionClassification
Aimless0.5.31data scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
Aimlessdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ssb

6ssb


Resolution: 1.47→62.52 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.957 / SU R Cruickshank DPI: 0.074 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.08 / SU Rfree Blow DPI: 0.077 / SU Rfree Cruickshank DPI: 0.072
RfactorNum. reflection% reflectionSelection details
Rfree0.208 2487 5.11 %RANDOM
Rwork0.19 ---
obs0.191 48684 88.8 %-
Displacement parametersBiso max: 112.45 Å2 / Biso mean: 29.18 Å2 / Biso min: 11.49 Å2
Baniso -1Baniso -2Baniso -3
1-1.7283 Å20 Å20 Å2
2--1.8128 Å20 Å2
3----3.5411 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: final / Resolution: 1.47→62.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2094 0 32 350 2476
Biso mean--17.79 44.93 -
Num. residues----269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d741SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes45HARMONIC2
X-RAY DIFFRACTIONt_gen_planes320HARMONIC5
X-RAY DIFFRACTIONt_it2206HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion272SEMIHARMONIC5
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_contact2567SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2206HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2996HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion3.22
X-RAY DIFFRACTIONt_other_torsion16.88
Refinement TLS params.Method: refined / Origin x: 3.9676 Å / Origin y: 10.6993 Å / Origin z: 20.0582 Å
111213212223313233
T-0.05 Å2-0.0036 Å20.007 Å2--0.0526 Å20.0107 Å2---0.0584 Å2
L1.1548 °20.0552 °2-0.6358 °2-1.6219 °2-0.2539 °2--0.7445 °2
S-0.0262 Å °-0.0709 Å °0.0074 Å °-0.0171 Å °0.0291 Å °-0.0442 Å °0.049 Å °0.074 Å °-0.0028 Å °
Refinement TLS groupSelection details: { A|* }

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