5Y5U

Crystal structures of spleen tyrosine kinase in complex with a novel inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.14 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.239 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors.

Lee, S.J.Choi, J.S.Bong, S.M.Hwang, H.J.Lee, J.Song, H.J.Lee, J.Kim, J.H.Koh, J.S.Lee, B.I.

(2018) Mol Cells 41: 545-552

  • DOI: https://doi.org/10.14348/molcells.2018.2219
  • Primary Citation of Related Structures:  
    5Y5T, 5Y5U

  • PubMed Abstract: 

    Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials. Here, we report the crystal structures of SYK in complex with two newly developed inhibitors possessing 4-aminopyrido[4,3-D]pyrimidine moieties (SKI-G-618 and SKI-O-85). One SYK inhibitor (SKI-G-618) exhibited moderate inhibitory activity against SYK, whereas the other inhibitor (SKI-O-85) exhibited a low inhibitory profile against SYK. Binding mode analysis indicates that a highly potent SYK inhibitor might be developed by modifying and optimizing the functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK. In agreement with our structural analysis, one of our SYK inhibitor (SKI-G-618) shows strong inhibitory activities on the β -hexosaminidase release and phosphorylation of SYK/Vav in RBL-2H3 cells. Taken together, our findings have important implications for the design of high affinity SYK inhibitors.


  • Organizational Affiliation

    Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Korea.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase SYK
A, B
293Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8OU
Query on 8OU

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-[(1-methylindazol-5-yl)amino]-2-(4-oxidanylpiperidin-1-yl)-8H-pyrido[4,3-d]pyrimidin-5-one
C20 H21 N7 O2
FQRDWNFNSKITIK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8OU Binding MOAD:  5Y5U IC50: 17.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.14 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.239 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.155α = 79.83
b = 42.013β = 90.78
c = 87.66γ = 79.6
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-27
    Type: Initial release
  • Version 1.1: 2018-07-11
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Refinement description