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Evidence for a global inhibitor-induced conformation change on the Ca2+-ATPase of sarcoplasmic reticulum from paired inhibitor studies

Evidence for a global inhibitor-induced conformation change on the Ca2+-ATPase of sarcoplasmic reticulum from paired inhibitor studies
Evidence for a global inhibitor-induced conformation change on the Ca2+-ATPase of sarcoplasmic reticulum from paired inhibitor studies
The Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum is inhibited by a variety of hydrophobic, hydroxy-containing molecules. A kinetic method has been used to study competition between binding of pairs of inhibitors to the ATPase. The presence of 2,5-di-tert-butyl-1,4-dihydroxybenzene (BHQ) decreases the affinity of the ATPase for 2,5-dipropyl-1,4-dihydroxybenzene (PHQ), suggesting that PHQ and BHQ bind to the same site on the ATPase. In contrast, the presence of BHQ increases the affinity of the ATPase for curcumin and vice versa. This suggests that BHQ and curcumin bind to separate sites on the ATPase and that binding of the first inhibitor to the ATPase results in a change to a conformation with higher affinity for the second inhibitor. This is consistent with previous experiments with BHQ and thapsigargin suggesting a conformation change on inhibitor binding, E2 + I E2I E2AI, with E2AI having a higher affinity for the second inhibitor than E2. The affinity for BHQ is also increased by binding of diethylstilbesterol, ellagic acid, or nonylphenol, and the affinity for curcumin is also increased by ellagic acid. These results showing that binding of a variety of inhibitors of very different structures all result in a general increase in inhibitor affinity point to a global conformational change on the Ca2+-ATPase caused by inhibitor binding, as well as any local, inhibitor-specific changes in conformation.
0006-2960
2869-2875
Logan-Smith, Melanie J.
b105b7db-0711-4fa1-bcf2-35d0c3c159b1
East, J. Malcolm
9fe7f794-1d89-4935-9a99-b831d786056e
Lee, Anthony G.
0891914c-e0e2-4ee1-b43e-1b70eb072d8e
Logan-Smith, Melanie J.
b105b7db-0711-4fa1-bcf2-35d0c3c159b1
East, J. Malcolm
9fe7f794-1d89-4935-9a99-b831d786056e
Lee, Anthony G.
0891914c-e0e2-4ee1-b43e-1b70eb072d8e

Logan-Smith, Melanie J., East, J. Malcolm and Lee, Anthony G. (2002) Evidence for a global inhibitor-induced conformation change on the Ca2+-ATPase of sarcoplasmic reticulum from paired inhibitor studies. Biochemistry, 41 (8), 2869-2875. (doi:10.1021/bi011938n).

Record type: Article

Abstract

The Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum is inhibited by a variety of hydrophobic, hydroxy-containing molecules. A kinetic method has been used to study competition between binding of pairs of inhibitors to the ATPase. The presence of 2,5-di-tert-butyl-1,4-dihydroxybenzene (BHQ) decreases the affinity of the ATPase for 2,5-dipropyl-1,4-dihydroxybenzene (PHQ), suggesting that PHQ and BHQ bind to the same site on the ATPase. In contrast, the presence of BHQ increases the affinity of the ATPase for curcumin and vice versa. This suggests that BHQ and curcumin bind to separate sites on the ATPase and that binding of the first inhibitor to the ATPase results in a change to a conformation with higher affinity for the second inhibitor. This is consistent with previous experiments with BHQ and thapsigargin suggesting a conformation change on inhibitor binding, E2 + I E2I E2AI, with E2AI having a higher affinity for the second inhibitor than E2. The affinity for BHQ is also increased by binding of diethylstilbesterol, ellagic acid, or nonylphenol, and the affinity for curcumin is also increased by ellagic acid. These results showing that binding of a variety of inhibitors of very different structures all result in a general increase in inhibitor affinity point to a global conformational change on the Ca2+-ATPase caused by inhibitor binding, as well as any local, inhibitor-specific changes in conformation.

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More information

Submitted date: 16 October 2001
Published date: 1 February 2002

Identifiers

Local EPrints ID: 56820
URI: http://eprints.soton.ac.uk/id/eprint/56820
ISSN: 0006-2960
PURE UUID: 99c964d3-417e-48c8-a506-bb54323290d6

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Date deposited: 07 Aug 2008
Last modified: 15 Mar 2024 11:03

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Contributors

Author: Melanie J. Logan-Smith
Author: J. Malcolm East
Author: Anthony G. Lee

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