Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase
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Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase. / Skytte, Dorthe Mondrup; Møller, Jesper Vuust; Liu, Huizhen; Nielsen, Helle Østergren; Svenningsen, Louise Elsa; Jensen, Christina Mernøe; Olsen, Carl Erik; Christensen, Søren Brøgger.
I: Bioorganic & Medicinal Chemistry, Bind 18, Nr. 15, 2010, s. 5634-5646.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase
AU - Skytte, Dorthe Mondrup
AU - Møller, Jesper Vuust
AU - Liu, Huizhen
AU - Nielsen, Helle Østergren
AU - Svenningsen, Louise Elsa
AU - Jensen, Christina Mernøe
AU - Olsen, Carl Erik
AU - Christensen, Søren Brøgger
N1 - Keywords: Thapsigargin; SERCA; Pharmacophore; Topography of binding cavity
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Former LIFE faculty
U2 - 10.1016/j.bmc.2010.06.032
DO - 10.1016/j.bmc.2010.06.032
M3 - Journal article
C2 - 20615710
VL - 18
SP - 5634
EP - 5646
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 15
ER -
ID: 21858685