4PX6

SYK catalytic domain in complex with a potent pyridopyrimidinone inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 

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Ligand Structure Quality Assessment 


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


Literature

Syk inhibitors with high potency in presence of blood.

Thoma, G., Blanz, J., Buhlmayer, P., Druckes, P., Kittelmann, M., Smith, A.B., van Eis, M., Vangrevelinghe, E., Zerwes, H.G., Che, J.J., He, X., Jin, Y., Lee, C.C., Michellys, P.Y., Uno, T., Liu, H.

(2014) Bioorg Med Chem Lett 24: 2278-2282

  • DOI: https://doi.org/10.1016/j.bmcl.2014.03.075
  • Primary Citation of Related Structures:  
    4PX6

  • PubMed Abstract: 

    We describe two series of Syk inhibitors which potently abrogate Syk kinase function in enzymatic assays, cellular assays and in primary cells in the presence of blood. Introduction of a 7-aminoindole substituent led to derivatives with good kinase selectivity and little or no hERG channel inhibition (3b, 10c).

    • Organizational Affiliation: 

    Novartis Institutes for Biomedical Research, Forum 1 Novartis Campus, 4056 Basel, Switzerland. Electronic address: gebhard.thoma@novartis.com.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase SYK291Homo sapiensMutation(s): 1 
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
2X6
Query on 2X6
Download Ideal Coordinates CCD File 
B [auth A]7-{[(1R,2S)-2-aminocyclohexyl]amino}-5-(1H-indol-7-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one
C21 H23 N7 O
JZLUCFJMWJDRIK-UONOGXRCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2X6 BindingDB:  4PX6 IC50: min: 4, max: 307 (nM) from 3 assay(s)
Binding MOAD:  4PX6 IC50: 4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.889α = 90
b = 85.161β = 90
c = 88.961γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
BUSTERrefinement
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2014-04-23 
    • Deposition Author(s): Lee, C.C.

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-23
    Type: Initial release
  • Version 1.1: 2014-05-21
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description