title: Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Dorthe Mondrup
authors.initials: DM
authors.lastname: Skytte
authors.forename: Jesper Vuust
authors.initials: JV
authors.lastname: Møller
authors.forename: Huizhen
authors.initials: H
authors.lastname: Liu
authors.forename: Helle Østergren
authors.initials: HØ
authors.lastname: Nielsen
authors.forename: Louise Elsa
authors.initials: LE
authors.lastname: Svenningsen
authors.forename: Christina Mernøe
authors.initials: CM
authors.lastname: Jensen
authors.forename: Carl Erik
authors.initials: CE
authors.lastname: Olsen
authors.forename: Søren Brøgger
authors.initials: SB
authors.lastname: Christensen
mesh_terms: 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
chemical_list: D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases