Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase.
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.
Skytte
Dorthe Mondrup
DM
Department of Medicinal Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
Møller
Jesper Vuust
JV
Liu
Huizhen
H
Nielsen
Helle Østergren
HØ
Svenningsen
Louise Elsa
LE
Jensen
Christina Mernøe
CM
Olsen
Carl Erik
CE
Christensen
Søren Brøgger
SB
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000737:chemistry / Q000378:metabolism*; D019284:Thapsigargin / Q000737:chemistry* / Q000494:pharmacology
D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases