Tharindunee Jayakody, Asuka Inoue, Srinivasaraghavan Kannan, Gaku Nakamura, Kouki Kawakami, Krishan Mendis, Thanh-Binh Nguyen, Jianguo Li, Deron R. Herr, Chandra S. Verma, Gavin S. Dawe
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引用次数: 0
Abstract
The neuropeptide relaxin-3 is composed of an A chain and a B chain held together by disulfide bonds, and it modulates functions such as anxiety and food intake by binding to and activating its cognate receptor RXFP3, mainly through the B chain. Biased ligands of RXFP3 would help to determine the molecular mechanisms underlying the activation of G proteins and β-arrestins downstream of RXFP3 that lead to such diverse functions. We showed that the i, i+4 stapled relaxin-3 B chains, 14s18 and d(1-7)14s18, were Gαi/o-biased agonists of RXFP3. These peptides did not induce recruitment of β-arrestin1/2 to RXFP3 by GPCR kinases (GRKs), in contrast to relaxin-3, which enabled the GRK2/3-mediated recruitment of β-arrestin1/2 to RXFP3. Relaxin-3 and the previously reported peptide 4 (an i, i+4 stapled relaxin-3 B chain) did not exhibit biased signaling. The staple linker of peptide 4 and parts of both the A chain and B chain of relaxin-3 interacted with extracellular loop 3 (ECL3) of RXFP3, moving it away from the binding pocket, suggesting that unbiased ligands promote a more open conformation of RXFP3. These findings highlight roles for the A chain and the N-terminal residues of the B chain of relaxin-3 in inducing conformational changes in RXFP3, which will help in designing selective biased ligands with improved therapeutic efficacy.
期刊介绍:
"Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets.
The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment.
In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.