6HM7

CRYSTAL STRUCTURE OF SPLEEN TYROSINE KINASE (SYK) IN COMPLEX WITH A 2-(PHENOXYMETHYL)PYRIDINE INHIBITOR

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

Starting Model: other
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease.

Barker, M.D., Liddle, J., Atkinson, F.L., Wilson, D.M., Dickson, M.C., Ramirez-Molina, C., Lewis, H., Davis, R.P., Somers, D.O., Neu, M., Jones, E., Watson, R.

(2018) Bioorg Med Chem Lett 28: 3458-3462

  • DOI: https://doi.org/10.1016/j.bmcl.2018.09.022
  • Primary Citation of Related Structures:  
    6HM6, 6HM7

  • PubMed Abstract: 

    The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.

    • 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 SYK276Homo 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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GDH
Query on GDH
Download Ideal Coordinates CCD File 
B [auth A]7-[2-methoxy-6-[(4-methylpyridin-2-yl)methoxy]phenyl]-2,3,4,5-tetrahydro-1~{H}-3-benzazepine
C24 H26 N2 O2
KYANYGKXMNYFBX-UHFFFAOYSA-N
GOL
Query on GOL
Download Ideal Coordinates CCD File 
F [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
BR
Query on BR
Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A]		BROMIDE ION
Br
CPELXLSAUQHCOX-UHFFFAOYSA-M
DMS
Query on DMS
Download Ideal Coordinates CCD File 
G [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-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
GDH BindingDB:  6HM7 IC50: min: 79, max: 200 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.114α = 90
b = 84.892β = 100.16
c = 40.361γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
PDB_EXTRACTdata extraction
REFMACphasing
REFMACrefinement
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2018-10-10 
    • Deposition Author(s): Somers, D.O.

Revision History  (Full details and data files)

  • Version 1.0: 2018-10-10
    Type: Initial release
  • Version 1.1: 2018-10-17
    Changes: Data collection, Database references
  • Version 1.2: 2024-05-01
    Changes: Data collection, Database references, Refinement description
  • Version 1.3: 2024-11-20
    Changes: Structure summary