PUBLICATION
Structure-guided discovery of Otopetrin 1 inhibitors reveals druggable binding sites at the intrasubunit interface
- Authors
- Burendei, B., Kaplan, J.P., Orellana, G.M., Liman, E.R., Forli, S., Ward, A.B.
- ID
- ZDB-PUB-251024-10
- Date
- 2025
- Source
- Nature communications 16: 93629362 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- Cryoelectron Microscopy
- Drug Discovery
- HEK293 Cells
- Humans
- Ion Channels*/antagonists & inhibitors
- Ion Channels*/chemistry
- Ion Channels*/genetics
- Ion Channels*/metabolism
- Molecular Docking Simulation
- Patch-Clamp Techniques
- Zebrafish
- Zebrafish Proteins*/antagonists & inhibitors
- Zebrafish Proteins*/chemistry
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 41130946 Full text @ Nat. Commun.
Citation
Burendei, B., Kaplan, J.P., Orellana, G.M., Liman, E.R., Forli, S., Ward, A.B. (2025) Structure-guided discovery of Otopetrin 1 inhibitors reveals druggable binding sites at the intrasubunit interface. Nature communications. 16:93629362.
Abstract
Proton conductance across cell membranes serves many biological functions, ranging from the regulation of intracellular and extracellular pH to the generation of electrical signals that lead to sour taste perception. Otopetrins (OTOPs) are a conserved, eukaryotic family of proton-selective ion channels, one of which (OTOP1) serves as a gustatory sensor for sour tastes and ammonium chloride. As the functional properties and structures of OTOP channels were only recently described, there are presently few tools available to modulate their activity. Here, we perform subsequent rounds of molecular docking-based virtual screening against the structure of zebrafish OTOP1, followed by functional testing using whole-cell patch-clamp electrophysiology, and identify several small molecule inhibitors that are effective in the low-to-mid µM range. Cryo-electron microscopy structures reveal inhibitor binding sites in the intrasubunit interface that are validated by functional testing of mutant channels. Our findings reveal pockets that can be targeted for small molecule discovery to develop modulators for Otopetrins. Such modulators can serve as useful toolkit molecules for future investigations of structure-function relationships or physiological roles of Otopetrins.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping