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

DOI Web Site 参考文献89件
  • Tharindunee Jayakody
    Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Asuka Inoue
    Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
  • Gaku Nakamura
    Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
  • Srinivasaraghavan Kannan
    Bioinformatics Institute, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
  • Kouki Kawakami
    Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
  • Jianguo Li
    Bioinformatics Institute, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
  • Gavin S. Dawe
    Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Deron R. Herr
    Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Chandra S. Verma
    Bioinformatics Institute, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
  • Thanh-Binh Nguyen
    Bioinformatics Institute, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
  • Krishan Mendis
    Department of Chemistry, University of Colombo, P.O. Box 1490, Colombo 00300, Sri Lanka.

書誌事項

公開日
2024-02-13
資源種別
journal article
DOI
  • 10.1126/scisignal.abl5880
公開者
American Association for the Advancement of Science (AAAS)

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説明

<jats:p> 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 Gα <jats:sub>i/o</jats:sub> -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. </jats:p>

収録刊行物

  • Science Signaling

    Science Signaling 17 (823), 2024-02-13

    American Association for the Advancement of Science (AAAS)

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