Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design. (17th December 2018)

• Record Type: Journal Article
• Authors: Montini, Giulia; Booker, Jennifer; Sula, Altin; Wallace, B.A.
• Is Part Of: Biochemical Society transactions. Volume 46:Number 6(2018)
• Page Start: 1567
• Page End: 1575
• Publication Date: 2018-12-17
• Subjects: channel gating mechanism -- crystal structures -- fenestrations -- rational drug design -- sodium channels; Biochemistry -- Congresses; 572
• DOI: 10.1042/BST20180295
• Languages: English
• ISSNs: 0300-5127

Abstract

Abstract : Voltage-gated sodium channels (Navs) are responsible for the initiation of the action potential in excitable cells. Several prokaryotic sodium channels, most notably NavMs from Magnetococcus marinus and NavAb from Arcobacter butzleri, have been shown to be good models for human sodium channels based on their sequence homologies and high levels of functional similarities, including ion flux, and functional consequences of critical mutations. The complete full-length crystal structures of these prokaryotic sodium channels captured in different functional states have now revealed the molecular natures of changes associated with the gating process. These include the structures of the intracellular gate, the selectivity filter, the voltage sensors, the intra-membrane fenestrations, and the transmembrane (TM) pore. Here we have identified for the first time how changes in the fenestrations in the hydrophobic TM region associated with the opening of the intracellular gate could modulate the state-dependent ingress and binding of drugs in the TM cavity, in a way that could be exploited for rational drug design.