Sarafotoxins (SRTXs) are endothelin-like peptides extracted from snake venom. SRTXs stimulate the endothelin ETA and ETB receptors and enhance vasoconstriction, followed by left ventricular dysfunction and bronchoconstriction. SRTXs include four major isopeptides, S6a-d, with different subtype selectivities. Here, we report the crystal structure of the human ETB receptor in complex with the non-selective sarafotoxin S6b at 3.0 Å resolution. This structure reveals the similarities and differences between the binding modes of the endothelins and S6b. Moreover, molecular dynamics simulations based on the S6b-bound receptor provides structural insight into the subtype selectivity of the sarafotoxins. Our study clarifies the recognition mechanism of the endothelin-like peptide families.