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TitleStructure-guided discovery of Otopetrin 1 inhibitors reveals druggable binding sites at the intrasubunit interface.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 9362, Year 2025
Publish dateOct 23, 2025
AuthorsBatuujin Burendei / Joshua P Kaplan / Gerardo M Orellana / Emily R Liman / Stefano Forli / Andrew B Ward /
PubMed AbstractProton 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 ...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.
External linksNat Commun / PubMed:41130946 / PubMed Central
MethodsEM (single particle)
Resolution3.23 - 3.73 Å
Structure data

48227

9mff

EMDB-48227, PDB-9mff:
Structure of zebrafish OTOP1 in nanodisc in complex with inhibitor C2.2
Method: EM (single particle) / Resolution: 3.23 Å

48234

9mfl

EMDB-48234, PDB-9mfl:
Structure of zebrafish OTOP1 in nanodisc in the presence of inhibitor C11
Method: EM (single particle) / Resolution: 3.73 Å

48235

9mfm

EMDB-48235, PDB-9mfm:
Structure of zebrafish OTOP1 in nanodisc in complex with inhibitor C2.36
Method: EM (single particle) / Resolution: 3.42 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

PDB-1bku:
EFFECTS OF GLYCOSYLATION ON THE STRUCTURE AND DYNAMICS OF EEL CALCITONIN, NMR, 10 STRUCTURES

ChemComp-CLR:
CHOLESTEROL

ChemComp-QNJ:
(3beta,5beta,14beta,17alpha)-cholestan-3-ol

PDB-1bkt:
BMKTX TOXIN FROM SCORPION BUTHUS MARTENSII KARSCH, NMR, 25 STRUCTURES

Source
  • danio rerio (zebrafish)
KeywordsMEMBRANE PROTEIN / proton channel / ion channel / OTOP / Otopetrin

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