Sula, A;
Hollingworth, D;
Ng, LCT;
Larmore, M;
DeCaen, PG;
Wallace, BA;
(2021)
A tamoxifen receptor within a voltage-gated sodium channel.
Molecular Cell
10.1016/j.molcel.2020.12.048.
(In press).
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Abstract
Voltage-gated sodium channels are targets for many analgesic and antiepileptic drugs whose therapeutic mechanisms and binding sites have been well characterized. We describe the identification of a previously unidentified receptor site within the NavMs voltage-gated sodium channel. Tamoxifen, an estrogen receptor modulator, and its primary and secondary metabolic products bind at the intracellular exit of the channel, which is a site that is distinct from other previously characterized sodium channel drug sites. These compounds inhibit NavMs and human sodium channels with similar potencies and prevent sodium conductance by delaying channel recovery from the inactivated state. This study therefore not only describes the structure and pharmacology of a site that could be leveraged for the development of new drugs for the treatment of sodium channelopathies but may also have important implications for off-target health effects of this widely used therapeutic drug.
| Type: | Article |
|---|---|
| Title: | A tamoxifen receptor within a voltage-gated sodium channel |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.molcel.2020.12.048 |
| Publisher version: | https://doi.org/10.1016/j.molcel.2020.12.048 |
| Language: | English |
| Additional information: | This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Channelopathies, Crystal Structure, Drug Binding, Electrophysiology, Estrogen Receptor, Novel Binding Site, Off-Target Drug Effects, Pharmacology, Tamoxifen, Voltage-gated Sodium Channels |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10121429 |
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