Mark J Arcario, Christopher G Mayne, and Emad Tajkhorshid.
A membrane-embedded pathway delivers general anesthetics to two
interacting binding sites in the Gloeobacter violaceus ion channel.
Journal of Biological Chemistry, 9:9480-9492, 2017.
(PMC: PMC5465477)
ARCA2017-ET
General anesthetics exert their effects on the central nervous system by acting
on ion channels, most notably pentameric ligand−gated ion channels (pLGICs).
Although numerous studies have focused on pLGICs, the details of anesthetic
binding and channel modulation remains debated. A better understanding of
anesthetic mechanism of action is necessary for the development of safer and
more efficacious drugs. Herein, we present a computational study identifying
two anesthetic binding sites in the transmembrane domain of the GLIC channel,
characterize the putative binding pathway, and observe structural changes
associated with channel function. Molecular simulations of desflurane reveal a
binding pathway to GLIC via a membrane−embedded tunnel utilizing an
intrasubunit protein lumen as the conduit, an observation that explains the
Meyer−Overton hypothesis, or why the lipophilicity of an anesthetic and its
potency are generally proportional. Moreover, employing high concentrations of
ligand led to the identification of a second transmembrane site (TM2) which
inhibits dissociation of anesthetic from the TM1 site, and is consistent with the
high concentrations of anesthetics required to achieve clinical effects. Finally,
asymmetric binding patterns of anesthetic to the channel were found to promote
an iris−like conformational change that constricts and dehydrates the ion pore,
creating a 13.5 kcal/mol barrier to ion translocation. Together with previous
studies, the simulations presented herein demonstrate a novel anesthetic
binding site in GLIC which is accessed through a membrane-embedded tunnel
and interacts with a previously known site, resulting in conformational changes
that produce a non−conductive state of the channel.
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