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bioRxiv · 10.1101/2024.05.02.592243

Vestibular modulation by stimulant derivatives in a pentameric ligand-gated ion channel

Karlsson, E.·Anden, O.·Fan, C.·Fourati, Z.·Haouz, A.·Zhuang, Y.·Howard, R. J.·Delarue, M.·Lindahl, E.
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Abstract

Allosteric modulation of pentameric ligand-gated ion channels (pLGICs) is critical to the action of neurotransmitters and many psychoactive drugs. However, details of their modulatory mechanisms remain unclear, especially beyond the orthosteric neurotransmitter-binding sites. The recently reported prokaryotic channel sTeLIC, a pH-gated homolog of eukaryotic receptors in the pLGIC family, is thought to be modulated by aromatic compounds via a relatively uncharacterized modulatory site in the extracellular vestibule. Here, we show that sTeLIC is sensitive to potentiation by psychostimulant derivatives. By determining new cryo-EM and X-ray structures in closed and open states, and testing the impact of targeted mutations on electrophysiological behavior, we show that several amphiphilic compounds preferentially bind a vestibular pocket in the contracted open-state extracellular domain. This work provides a detailed structure-function mechanism for allosteric potentiation via a noncanonical lig- and site, with potential conservation in eukaryotic pentameric ligand-gated ion channels.

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Karlsson, E., Anden, O., Fan, C., Fourati, Z., Haouz, A., Zhuang, Y., Howard, R. J., Delarue, M., Lindahl, E.. 2024-05-05. Vestibular modulation by stimulant derivatives in a pentameric ligand-gated ion channel. https://doi.org/10.1101/2024.05.02.592243

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