Logo image
Back
Structural underpinnings of human Slo1 inhibition by scorpion and fungal toxins
Journal article   Open access   Peer reviewed

Structural underpinnings of human Slo1 inhibition by scorpion and fungal toxins

Gopal S Kallure, Kamalendu Pal, Gabriel W Prather and Sandipan Chowdhury
Proceedings of the National Academy of Sciences - PNAS, Vol.123(38), e2606537123
09/22/2026
DOI: 10.1073/pnas.2606537123
PMCID: PMC13598261
PMID: 42735318
url
https://doi.org/10.1073/pnas.2606537123View
Published (Version of record) Open Access

Abstract

Slo1 channels regulate key electrochemical signaling events in a variety of excitable and nonexcitable cells. Here, we have investigated the mechanisms by which distinct small molecules inhibit human Slo1 (hSlo1) channel activity using single-particle cryo-EM, liposome flux, and toxin-binding assays. We find that unlike classical permeation blockers like scorpion toxins, indole diterpene (ID) class of fungal mycotoxins, paxilline and penitrem A, are ensconced in a binding pocket, deep within the putatively closed hSlo1 pore and sterically restrict its opening. Binding of paxilline to its gating inhibition site dramatically slows dissociation of a fluorescent charybdotoxin derivative, via an allosteric mechanism that likely involves a key residue on the S5 helix (W246). Although four paxilline molecules may concurrently engage the hSlo1 pore, binding of <4 molecules is sufficient for efficacious inhibition of channel opening but inefficient at arresting toxin dissociation. We also find evidence that under divalent and ID free conditions, the ID binding pocket of hSlo1 is occluded by lipids that extend into the hSlo1 pore lumen through interhelical crevices that become constricted in the divalent bound open state. These lipids may not only competitively regulate ID binding but also tune the energetics of channel gating, sterically or by altering the hydration state of the pore vestibule. Our study provides a framework to understand fundamental Slo1 gating mechanisms and aid future developments of therapeutically beneficial small molecule Slo1 inhibitors.
 Animals Binding Sites Charybdotoxin - chemistry Charybdotoxin - pharmacology Cryoelectron Microscopy Humans Indoles - chemistry Indoles - metabolism Indoles - pharmacology Ion Channel Gating - drug effects Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - antagonists & inhibitors Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - chemistry Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - genetics Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - metabolism Mycotoxins - chemistry Mycotoxins - pharmacology Protein Binding Scorpion Venoms - chemistry Scorpion Venoms - pharmacology Scorpions - chemistry

Details

Metrics

8 Record Views
Logo image