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

Dorthe Mondrup Skytte; Jesper Vuust Møller; Huizhen Liu; Helle Østergren Nielsen; Louise Elsa Svenningsen; Christina Mernøe Jensen; Carl Erik Olsen; Søren Brøgger Christensen

doi:10.1016/j.bmc.2010.06.032

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

Dorthe Mondrup Skytte, Jesper Vuust Møller, Huizhen Liu, Helle Østergren Nielsen, Louise Elsa Svenningsen, Christina Mernøe Jensen, Carl Erik Olsen, Søren Brøgger Christensen

Department of Chemistry

17 Citations (Scopus)

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.

Original language	English
Journal	Bioorganic & Medicinal Chemistry
Volume	18
Issue number	15
Pages (from-to)	5634-5646
Number of pages	13
ISSN	0968-0896
DOIs	https://doi.org/10.1016/j.bmc.2010.06.032
Publication status	Published - 1 Aug 2010

Keywords

Former LIFE faculty

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10.1016/j.bmc.2010.06.032

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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.",

keywords = "Former LIFE faculty",

author = "Skytte, {Dorthe Mondrup} and M{\o}ller, {Jesper Vuust} and Huizhen Liu and Nielsen, {Helle {\O}stergren} and Svenningsen, {Louise Elsa} and Jensen, {Christina Mern{\o}e} and Olsen, {Carl Erik} and Christensen, {S{\o}ren Br{\o}gger}",

note = "Keywords: Thapsigargin; SERCA; Pharmacophore; Topography of binding cavity",

year = "2010",

month = aug,

day = "1",

doi = "10.1016/j.bmc.2010.06.032",

language = "English",

volume = "18",

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journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

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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 - 2010/8/1

Y1 - 2010/8/1

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

SN - 0968-0896

VL - 18

SP - 5634

EP - 5646

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 15

ER -

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

Abstract

Keywords

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