Mechanisms of biased agonism by Gα i/o -biased stapled peptide agonists of the relaxin-3 receptor

• DOI: 10.1126/scisignal.abl5880
• Publication Date: 2024-02-13T18:58:12Z
• Authors: Tharindunee Jayakody; Asuka Inoue; Srinivasaraghavan...; Gaku Nakamura; Kouki Kawakami; Krishan Mendis; Thanh-Binh Nguyen; Jianguo Li; Deron R. Herr; Chandra S. Verma; Gavin S. Dawe
• Keywords: Relaxin; Linker; Functional selectivity

The neuropeptide relaxin-3 is composed of an A chain and a B held together by disulfide bonds, it modulates functions such as anxiety food intake binding to activating its cognate receptor RXFP3, mainly through the chain. Biased ligands RXFP3 would help determine molecular mechanisms underlying activation G proteins β-arrestins downstream that lead diverse functions. We showed i, i+4 stapled chains, 14s18 d(1-7)14s18, were Gα i/o -biased agonists RXFP3. These peptides did not induce recruitment β-arrestin1/2 GPCR kinases (GRKs), in contrast relaxin-3, which enabled GRK2/3-mediated Relaxin-3 previously reported peptide 4 (an chain) exhibit biased signaling. staple linker parts both interacted with extracellular loop 3 (ECL3) moving away from pocket, suggesting unbiased promote more open conformation findings highlight roles for N-terminal residues inducing conformational changes will designing selective improved therapeutic efficacy.