5LMB

HUMAN SPLEEN TYROSINE KINASE KINASE DOMAIN IN COMPLEX WITH AZANAPHTHYRIDINE INHIBITOR

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 

Starting Model: other
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history. 


Literature

Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors.

Garton, N.S., Barker, M.D., Davis, R.P., Douault, C., Hooper-Greenhill, E., Jones, E., Lewis, H.D., Liddle, J., Lugo, D., McCleary, S., Preston, A.G., Ramirez-Molina, C., Neu, M., Shipley, T.J., Somers, D.O., Watson, R.J., Wilson, D.M.

(2016) Bioorg Med Chem Lett 26: 4606-4612

  • DOI: https://doi.org/10.1016/j.bmcl.2016.08.070
  • Primary Citation of Related Structures:  
    5LMA, 5LMB

  • PubMed Abstract: 

    The optimisation of the azanaphthyridine 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 hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.

    • Organizational Affiliation: 

    GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. Electronic address: [email protected].


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase SYK
A, B
277Homo 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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6ZF
Query on 6ZF
Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]		7-[6-(dimethylamino)pyridin-3-yl]-~{N}-[[(3~{S})-piperidin-3-yl]methyl]pyrido[3,4-b]pyrazin-5-amine
C20 H25 N7
CLKZDZYGBHNPSM-AWEZNQCLSA-N
GOL
Query on GOL
Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
J [auth B],
K [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
6ZF BindingDB:  5LMB IC50: min: 16, max: 316 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.849α = 99.81
b = 41.78β = 90.41
c = 86.991γ = 100.03
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
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: 2016-09-14
    Type: Initial release
  • Version 1.1: 2016-09-21
    Changes: Database references
  • Version 1.2: 2019-04-03
    Changes: Data collection, Source and taxonomy
  • Version 1.3: 2024-05-01
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2024-11-06
    Changes: Structure summary