Structural Pharmacology of Voltage-Gated Sodium Channels. Issue 17 (20th August 2021)

• Record Type: Journal Article
• Authors: Noreng, Sigrid; Li, Tianbo; Payandeh, Jian
• Is Part Of: Journal of molecular biology. Volume 433:Issue 17(2021)
• Publication Date: 2021-08-20
• Subjects: Sodium channel -- Pharmacology -- Structure -- Drug discovery; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.166967
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: High-resolution structures of eukaryotic NaV channels have been determined. Complexes with drugs and peptide toxins reveal the basis for channel modulation. Insights into ion selectivity, voltage-sensing and channel gating have been obtained. Implications for drug design and discovery are discussed. Abstract: Voltage-gated sodium (NaV ) channels initiate and propagate action potentials in excitable tissues to mediate key physiological processes including heart contraction and nervous system function. Accordingly, NaV channels are major targets for drugs, toxins and disease-causing mutations. Recent breakthroughs in cryo-electron microscopy have led to the visualization of human NaV 1.1, NaV 1.2, NaV 1.4, NaV 1.5 and NaV 1.7 channel subtypes at high-resolution. These landmark studies have greatly advanced our structural understanding of channel architecture, ion selectivity, voltage-sensing, electromechanical coupling, fast inactivation, and the molecular basis underlying NaV channelopathies. NaV channel structures have also been increasingly determined in complex with toxin and small molecule modulators that target either the pore module or voltage sensor domains. These structural studies have provided new insights into the mechanisms of pharmacological action and opportunities for subtype-selective NaV channel drug design. This review will highlight the structural pharmacology of human NaV channels as well as the potential use of engineered and chimeric channels in future drug discovery efforts.