Structural determination of human Na v 1.4 and Na v 1.7 using single particle cryo-electron microscopy

TitleStructural determination of human Na v 1.4 and Na v 1.7 using single particle cryo-electron microscopy
Publication TypeJournal Article
Year of Publication2021
AuthorsShen, H, Yan, N, Pan, X
JournalMethods Enzymol
Volume653
Pagination103-120
Date Published2021
ISSN1557-7988
KeywordsAction Potentials, Cryoelectron Microscopy, Humans, Sodium
Abstract

Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. Their abnormal functions are associated with numerous diseases, such as epilepsy, cardiac arrhythmia, and pain syndromes. Therefore, these channels represent important drug targets. Even in the post-resolution revolution era, a lack of structural information continues to impede structure-based drug discovery. The limiting factor for the structural determination of Nav channels using single particle cryo-electron microscopy (cryo-EM) resides in the generation of sufficient high-quality recombinant proteins. After extensive trials, we have been successful in determining a series of high-resolution structures of Nav channels, including NavPaS from American cockroach, Nav1.4 from electric eel, and human Nav1.1, Nav1.2, Nav1.4, Nav1.5, and Nav1.7, with distinct strategies. These structures established the framework for understanding the electromechanical coupling and disease mechanism of Nav channels, and for facilitating drug discovery. Here, we exemplify these methods with two specific cases, human Nav1.4 and Nav1.7, which may shed light on the structural determination of other membrane proteins.

DOI10.1016/bs.mie.2021.03.010
Alternate JournalMethods Enzymol
PubMed ID34099168