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Publication Abstract from PubMed

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 strategy. Hydrophobic interactions between RES-701-3 and the transmembrane region of the receptor, especially involving two tryptophan residues, play a crucial role in RES-701-3 binding. Furthermore, RES-701-3 prevents conformational changes associated with G-protein coupling, explaining its inverse agonist activity. A comparative analysis with other lasso peptides and their target proteins highlights the potential of lasso peptides as precise drug candidates for G-protein-coupled receptors. This structural insight into RES-701-3 binding to ET(B) receptor offers valuable information for the development of novel therapeutics targeting this receptor and provides a broader understanding of lasso peptide interactions with human cell-surface receptors.

Structure of a lasso peptide bound ET(B) receptor provides insights into the mechanism of GPCR inverse agonism.,Shihoya W, Akasaka H, Jordan PA, Lechner A, Okada BK, Costa Machado da Cruz G, Sano FK, Tanaka T, Kawahara R, Chaudhari R, Masamune H, Burk MJ, Nureki O Nat Commun. 2025 Apr 22;16(1):3446. doi: 10.1038/s41467-025-57960-x. PMID:40263271^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.