Molecular modelling of voltage-gated potassium, sodium and calcium channels complexed with metal ions and small-molecule ligands.

摘要

Voltage-gated potassium, sodium, and calcium channels play fundamental roles in cell physiology. They are targets for numerous drugs that are used to treat pain, cardiovascular, autoimmune, and other disorders. Atomic-resolution structures of ion channels and their complexes with ligands are necessary to understand the mechanisms of drug action of ligands. Electrophysiological and crystallographic studies have advanced our understanding of ion channels, but the binding sites, access pathways, and the mechanism of state-dependent action of medically important drugs remain unclear. During my graduate studies, I investigated the structure-function relationships of voltage-gated ion channels and their complexes with drugs by using energy calculations with experimental constraints. My work has helped resolve controversial interpretations of experiments addressing structural similarity between prokaryotic and eukaryotic K + channels. Our model of the open Shaker K + channel was confirmed by the later published X-ray structure of Kv1.2. Our Cav2.1 model reinterprets substituted-cysteine accessibility experiments, validates the proposed alignment between K + and Ca2+ channels, and suggests a similar folding of voltage-gated K+ and Ca2+ channels. These results allowed me to model eukaryotic K+ and Na+ channels in the resting and open/slow-inactivated states, and to predict the binding sites of local anaesthetics, correolide, and chromanol 293B. In these studies, we proposed the involvement of metal ions in the binding of nucleophilic drugs and suggested that the deficiency of permeating ion(s) in the outer pore of the slow-inactivated channels stabilizes the ligands. Simultaneous studies of K+, Na+, and Ca2+ channels were advantageous because the information acquired from one family of ion channels was relevant to other families. My studies contributed to the growing knowledge about ion channels by offering structural information and suggesting mechanisms for the action of drugs.