Dynamic Basis for Drug Binding

From the October 16, 2018 issue of Proceedings of the National Academy of Sciences of the USA (v. 115 pp. 10672–10677):

Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity

Stephanie A Heusser, Marie Lycksell, Xueqing Wang, Sarah E McComas, Rebecca J Howard & Erik Lindahl

Molecular mechanisms of general anesthetic modulation in pentameric ligand-gated ion channels remain controversial. Here we present molecular simulations and functional data that reveal correlations between dynamic differences in a membrane-accessible cavity and dramatic anesthetic effects, separate inhibitory and potentiating effects within the same electrophysiology recordings, and support a model for communication between the lipid bilayer and ion channel pore. In particular, enhanced electrostatic interactions in the membrane-accessible site were associated with a unique mode of anesthetic potentiation, persisting tens of minutes after washout. These results offer a bridge between lipid- and receptor-based theories of anesthesia, with the potential to inform both mechanistic understanding and drug development.

Read the full publication here.