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

Documents:
1-s2.0-S1097276520309904-main.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)