Novel Gurmarin-like Peptides fromGymnema sylvestreand their Interactions with the Sweet Taste Receptor T1R2/T1R3

Abstract

Gymnema sylvestre (GS) is a traditional medicinal plant known for its hypoglycemic and hypolipidemic effects. Gurmarin (hereafter Gur-1) is the only known peptide in GS. Gur-1 functions as a sweet taste suppressor in rodents but weakly in humans. Here, eight gurmarin-like peptides (Gur-2 to Gur-9) and their isoforms are reported in the GS transcriptome. The molecular mechanism of sweet taste suppression by Gur-1 is still largely unknown. Therefore, the complete architecture of human and mouse sweet taste receptor (STR) T1R2/T1R3 and its interaction with Gur-1 to Gur-9 were predicted by AlphaFold-Multimer (AF-M). Only Gur-1 and Gur-2 interact with T1R2 and T1R3 monomers and the T1R2/T1R3 heterodimer. AF-M predicted that Gur-1 binds to the intracellular domain (ICD) of the T1R2 monomer and to two binding sites in the cysteine rich domain (CRD) of the T1R3 monomer. In the T1R2/T1R3 heterodimer, Gur-1 binds to an additional site on the T1R2 subunit in addition to the ICD. The novel Gur-2 binds to two sites on the T1R2 monomer and one site on the T1R3 monomer, and as Gur-1 to two binding sites on the T1R2 subunit of the T1R2/T1R3 heterodimer. Furthermore, AF-M predicted that the Galpha-gustducin (a role in sweet taste transduction) interacts as Gur-1 with the ICD of the T1R2 subunit in the T1R2/T1R3 heterodimer, suggesting that Gur-1 may compete with Galpha-gustducin in the cell. These results highlight an unexpected diversity of gurmarin-like peptides in GS and provide the complete predicted architecture of the human and mouse sweet taste receptor with the putative binding sites of Gur-1, Gur-2 and Galpha-gustducin.