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Structure of zebrafish OTOP1 in nanodisc in the presence of inhibitor C11
Structural highlights
FunctionOTOP1_DANRE Proton-selective ion channel (PubMed:31160780). Biphasically modulated by acid and alkali, mediating proton influx and efflux in response to extracellular acid and base stimulation, respectively (By similarity). May be involved in acid and base perception (By similarity). Sensor for ammonium chloride (NH(4)Cl) in taste receptor cells. NH(4)Cl acts by increasing the intracellular pH, thereby generating a driving force for proton entry through OTOP1 channel (PubMed:37798269). Plays a role in the regulation of Ca(2+) flux in response to purigenic (ATP, ADP and UDP) stimuli, leading to increase in cytosolic Ca(2+) due to influx of extracellular calcium. May play this role by inhibiting P2Y purinoceptor-mediated Ca(2+) release in a Ca(2+)-dependent manner and promote an influx of Ca(2+) in response to ATP. Through this mechanism and possibly others, plays a role in the formation and function of calcium carbonate-based structures in the vestibular system of the inner ear, called otoconia, that sense gravity and linear acceleration (PubMed:15480759, PubMed:15581873).[UniProtKB:Q80VM9][1] [2] [3] [4] Publication Abstract from PubMedProton 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 microM 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. Structure-guided discovery of Otopetrin 1 inhibitors reveals druggable binding sites at the intrasubunit interface.,Burendei B, Kaplan JP, Orellana GM, Liman ER, Forli S, Ward AB Nat Commun. 2025 Oct 23;16(1):9362. doi: 10.1038/s41467-025-64392-0. PMID:41130946[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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