Article

Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase.

Department of Medicinal Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
Bioorganic & medicinal chemistry (impact factor: 2.82). 08/2010; 18(15):5634-46. DOI:10.1016/j.bmc.2010.06.032 pp.5634-46
Source: PubMed

ABSTRACT Removal of each of the acyl groups of thapsigargin at O-3, O-8 and O-10 significant reduces the affinity of the inhibitors to the SERCA1a pump. Replacement of the acyl groups at O-3 and O-10 with flexible residues could be performed with only a minor decrease of the affinity, whereas introduction of voluminous stiff residues caused dramatic reduction of the affinity. The results can be rationalized on the basis of the interactions of thapsigargin with the SERCA1a pump as revealed from 3D X-ray structural models of thapsigargin bound to the SERCA1a. In conclusion the results confirm and elaborate the previously suggested pharmocophore model of thapsigargin.

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Keywords

3D X-ray structural models
 
acyl groups
 
affinity
 
flexible residues
 
interactions
 
minor decrease
 
O-10 significant
 
SERCA1a
 
SERCA1a pump
 
suggested pharmocophore model
 
voluminous stiff residues