Structure of a lasso peptide bound ET_B receptor provides insights into the mechanism of GPCR inverse agonism.

ABSTRACT: Lasso peptides exhibit a unique lariat-like knotted structure imparting exceptional stability and thus show promise as therapeutic agents that target cell-surface receptors. One such receptor is the human endothelin type B receptor (ET_B), which is implicated in challenging cancers with poor immunotherapy responsiveness. The Streptomyces-derived lasso peptide, RES-701-3, is a selective inhibitor for ET_B and a compelling candidate for therapeutic development. However, meager production from a genetically recalcitrant host has limited further structure-activity relationship studies of this potent inhibitor. Here, we report cryo-electron microscopy structures of ET_B receptor in both its apo form and complex with RES-701-3, facilitated by a calcineurin-fusion st

SUBMITTER: Shihoya W 

PROVIDER: S-EPMC12015262 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature