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- PDB-4fz7: Crystal structure of spleen tyrosine kinase complexed with 6-((1R... -

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Basic information

Entry
Database: PDB / ID: 4fz7
TitleCrystal structure of spleen tyrosine kinase complexed with 6-((1R,2S)-2-Amino-cyclohexylamino)-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide
ComponentsTyrosine-protein kinase SYK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase 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 / 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
Chem-0VH / Tyrosine-protein kinase SYK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.75 Å
AuthorsKuglstatter, A. / Slade, M.
CitationJournal: J. Med. Chem. / Year: 2014
Title: Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.
Authors: Lucas, M.C. / Bhagirath, N. / Chiao, E. / Goldstein, D.M. / Hermann, J.C. / Hsu, P.Y. / Kirchner, S. / Kennedy-Smith, J.J. / Kuglstatter, A. / Lukacs, C. / Menke, J. / Niu, L. / Padilla, F. ...Authors: Lucas, M.C. / Bhagirath, N. / Chiao, E. / Goldstein, D.M. / Hermann, J.C. / Hsu, P.Y. / Kirchner, S. / Kennedy-Smith, J.J. / Kuglstatter, A. / Lukacs, C. / Menke, J. / Niu, L. / Padilla, F. / Peng, Y. / Polonchuk, L. / Railkar, A. / Slade, M. / Soth, M. / Xu, D. / Yadava, P. / Yee, C. / Zhou, M. / Liao, C.
History
DepositionJul 6, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Database references / Refinement description
Category: citation / citation_author / software
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _software.name / _software.version
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)34,2392
Polymers33,8841
Non-polymers3551
Water3,747208
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.630, 84.977, 88.607
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 33884.004 Da / Num. of mol.: 1 / Fragment: RESIDUES 365-635, PROTEIN KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYK / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P43405, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0VH / 6-{[(1R,2S)-2-aminocyclohexyl]amino}-4-[(6-ethylpyridin-2-yl)amino]pyridazine-3-carboxamide


Mass: 355.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H25N7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 44.13 %
Crystal growTemperature: 283 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 28% PEG 4000, 0.2M ammonium sulfate, 0.1M HEPES, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 283K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: RAYONIX MX225HE / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 1.67→44.3 Å / Num. obs: 35561 / % possible obs: 99.9 % / Observed criterion σ(I): 3 / Redundancy: 6.4 % / Biso Wilson estimate: 24.7 Å2 / Net I/σ(I): 11.8
Reflection shellResolution: 1.67→1.76 Å / Redundancy: 6.7 % / Mean I/σ(I) obs: 1.4 / Num. unique all: 5106 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
CNSrefinement
MOSFLMdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 3FQE

3fqe


Resolution: 1.75→42.49 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.92 / SU B: 6.331 / SU ML: 0.09 / Cross valid method: THROUGHOUT / ESU R: 0.125 / ESU R Free: 0.128 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24963 1552 5 %RANDOM
Rwork0.19991 ---
obs0.20243 29272 99.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.791 Å2
Baniso -1Baniso -2Baniso -3
1--0.25 Å20 Å20 Å2
2---0.36 Å20 Å2
3---0.6 Å2
Refinement stepCycle: LAST / Resolution: 1.75→42.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2163 0 26 208 2397
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.0222243
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9251.9733020
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2185261
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.85324.038104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.25915409
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8151512
X-RAY DIFFRACTIONr_chiral_restr0.1450.2315
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211674
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2921.51315
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.22522107
X-RAY DIFFRACTIONr_scbond_it3.4333928
X-RAY DIFFRACTIONr_scangle_it5.2964.5913
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.75→1.795 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.348 103 -
Rwork0.337 2164 -
obs--99.39 %
Refinement TLS params.Method: refined / Origin x: 3.5494 Å / Origin y: 10.4182 Å / Origin z: 19.8808 Å
111213212223313233
T0.0247 Å2-0.0053 Å20.0165 Å2-0.0211 Å2-0.0015 Å2--0.0249 Å2
L0.6687 °2-0.1459 °2-0.2618 °2-0.5822 °2-0.1113 °2--0.1633 °2
S-0.0257 Å °0.0219 Å °0.0018 Å °-0.0137 Å °0.004 Å °-0.026 Å °0.0266 Å °-0.0175 Å °0.0218 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1001 - 1208
2X-RAY DIFFRACTION1A701
3X-RAY DIFFRACTION1A363 - 639

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