Natural xanthones as α-Mangostin induce vasorelaxation via binding to key gating residues in the S6 domain of BK channels

Polyphenolic compounds are widely explored for health benefits, including hypertension, but their active ingredients, molecular targets, and mechanisms remain poorly defined. We identify the xanthone Mangostin from Garcinia mangostana as a potent modulator of several potassium channels, with large-conductance K⁺ (BK) channels as its primary target for vasorelaxation. Mangostin activated BK channels as α subunits alone, in complexes with vascular β1 subunits, and in reconstituted BKα/β1–Ca_v nanodomains. It shifted BK voltage activation to more negative potentials by antagonizing channel closure and promoting channel opening without markedly altering Ca²⁺ sensitivity. Docking, competition, single channel analysis and mutagenesis localized the binding site in the pore cavity below the SF, involving gating-critical S6 residues I308, L312, and A316, and suggest that Mangostin stays bound in closed and open states. These findings establish BK channel activation as the core molecular mechanism driving Mangostin’s vascular effects and define its structural mode of action, informing nutraceutical safety assessment and BK-targeted drug design.