9MFF
Structure of zebrafish OTOP1 in nanodisc in complex with inhibitor C2.2
This is a non-PDB format compatible entry.
Summary for 9MFF
| Entry DOI | 10.2210/pdb9mff/pdb |
| Related | 6nf4 6nf6 |
| EMDB information | 48227 9360 9361 |
| Descriptor | Proton channel OTOP1, CHOLESTEROL HEMISUCCINATE, 4-methyl-N-{2-[(2-methylprop-2-en-1-yl)oxy]phenyl}-1H-imidazole-5-carboxamide, ... (4 entities in total) |
| Functional Keywords | proton channel, ion channel, otop, otopetrin, membrane protein |
| Biological source | Danio rerio (zebrafish) |
| Total number of polymer chains | 2 |
| Total formula weight | 136986.08 |
| Authors | |
| Primary citation | Burendei, B.,Kaplan, J.P.,Orellana, G.M.,Liman, E.R.,Forli, S.,Ward, A.B. Structure-guided discovery of Otopetrin 1 inhibitors reveals druggable binding sites at the intrasubunit interface. Nat Commun, 16:9362-9362, 2025 Cited by PubMed 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. PubMed: 41130946DOI: 10.1038/s41467-025-64392-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.23 Å) |
Structure validation
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