4YJU

THE KINASE DOMAIN OF HUMAN SPLEEN TYROSINE (SYK) IN COMPLEX WITH GTC000249

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.168 

Starting Model: other
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor.

Liddle, J., Atkinson, F.L., Barker, M.D., Carter, P.S., Curtis, N.R., Davis, R.P., Douault, C., Dickson, M.C., Elwes, D., Garton, N.S., Gray, M., Hayhow, T.G., Hobbs, C.I., Jones, E., Leach, S., Leavens, K., Lewis, H.D., McCleary, S., Neu, M., Patel, V.K., Preston, A.G., Ramirez-Molina, C., Shipley, T.J., Skone, P.A., Smithers, N., Somers, D.O., Walker, A.L., Watson, R.J., Weingarten, G.G.

(2011) Bioorg Med Chem Lett 21: 6188-6194

  • DOI: https://doi.org/10.1016/j.bmcl.2011.07.082
  • Primary Citation of Related Structures:  
    3SRV, 4YJO, 4YJP, 4YJQ, 4YJR, 4YJS, 4YJT, 4YJU

  • PubMed Abstract: 

    The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.

    • Organizational Affiliation: 

    GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK. [email protected]


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase SYK281Homo sapiensMutation(s): 0 
Gene Names: SYK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P43405 (Homo sapiens)
Explore P43405 
Go to UniProtKB:  P43405
PHAROS:  P43405
GTEx:  ENSG00000165025 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43405
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4DO
Query on 4DO
Download Ideal Coordinates CCD File 
B [auth A]N~2~-(1,1-dioxido-2,3-dihydro-1,2-benzothiazol-6-yl)-5-fluoro-N~4~-(1H-indazol-4-yl)-N~4~-methylpyrimidine-2,4-diamine
C19 H16 F N7 O2 S
AKKNJEBKJABIRC-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
4DO BindingDB:  4YJU IC50: min: 1.99, max: 11.6 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.168 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.299α = 90
b = 87.233β = 92.15
c = 40.077γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
BUSTERrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-30
    Type: Initial release
  • Version 1.1: 2024-05-01
    Changes: Data collection, Database references, Refinement description
  • Version 1.2: 2024-11-13
    Changes: Structure summary