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A tamoxifen receptor within a voltage-gated sodium channel
DOI:
10.1016/j.molcel.2020.12.048
Authors:
Altin
Sula
(Birkbeck College, University of London)
,
David
Hollingworth
(Birkbeck College, University of London)
,
Leo C. T.
Ng
(Northwestern University)
,
Megan
Larmore
(Northwestern University)
,
Paul G.
Decaen
(Northwestern University)
,
Bonnie A.
Wallace
(Birkbeck, University of London)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Molecular Cell
, VOL 350
State:
Published (Approved)
Published:
January 2021
Diamond Proposal Number(s):
17201
,
23853

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.
Journal Keywords: Voltage-gated Sodium Channels; Tamoxifen; Estrogen Receptor; Crystal Structure; Electrophysiology; Drug Binding; Pharmacology; Novel Binding Site; Channelopathies; Off-Target Drug Effects
Diamond Keywords: Breast Cancer
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Added On:
03/02/2021 09:52
Documents:
1-s2.0-S1097276520309904-main.pdf
Discipline Tags:
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)