One pocket to activate them all: Efforts on understanding the modulator pocket in K2P channels

TL;DR

This review explores the modulator pocket in K2P channels, detailing its role in channel activation, ligand binding, and potential for targeted drug design, supported by experimental and computational evidence.

Contribution

It provides a comprehensive analysis of the modulator pocket's structure, function, and its role in gating mechanisms across K2P channels, proposing a common architectural model.

Findings

The modulator pocket is a conserved amphipathic site across K2P channels.

Ligand binding at this pocket influences channel gating and activity.

Structural variations in the pocket can be exploited for selective drug development.

Abstract

The modulator pocket is a cryptic site discovered in the TREK1 K2P channel that accommodates agonists capable of increasing the channel's activity. Since its discovery, equivalent sites in other K2P channels have been shown to bind various ligands, both endogenous and exogenous. In this review, we attempt to elucidate how the modulator pocket contributes to K2P channel activation. To this end, we first describe the gating mechanisms reported in the literature and rationalize their modes of action. We then highlight previous experimental and computational evidence for agonists that bind to the modulator pocket, together with mutations at this site that affect gating. Finally, we elaborate how the activation signal arising from the modulator pocket is transduced to the gates in K2P channels. In doing so, we outline a potential common modulator pocket architecture across K2P channels: a largely amphipathic structure -consistent with the expected properties of a pocket exposed at the interface between a hydrophobic membrane and the aqueous solvent- but still with some important channel-sequence-variations. This architecture and its key differences can be leveraged for the design of new selective and potent modulators.