Structural Insights into the Unique Modes of Relaxin-Binding and Tethered-Agonist Mediated Activation of RXFP1 and RXFP2

[Display omitted] •H2 relaxin has distinct and unique binding sites for RXFP1 and RXFP2.•Both the LDLa module and linker of RXFP1 and RXFP2 are essential for activation.•A conserved motif in the linker adopts different structures in RXFP1 and RXFP2.•These differences lead to distinct mechanisms for...

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Bibliographic Details
Published in:Journal of molecular biology 2021-10, Vol.433 (21), p.167217-167217, Article 167217
Main Authors: Sethi, Ashish, Bruell, Shoni, Ryan, Tim, Yan, Fei, Tanipour, Mohammad Hossein, Mok, Yee-Foong, Draper-Joyce, Chris, Khandokar, Yogesh, Metcalfe, Riley D., Griffin, Michael D.W., Scott, Daniel J., Hossain, Mohammad Akhter, Petrie, Emma J., Bathgate, Ross A.D., Gooley, Paul R.
Format: Article
Language:English
Subjects:
G protein-coupled receptor
peptide agonist
peptide-protein complex
protein conformational dynamics
solution NMR
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Summary:[Display omitted] •H2 relaxin has distinct and unique binding sites for RXFP1 and RXFP2.•Both the LDLa module and linker of RXFP1 and RXFP2 are essential for activation.•A conserved motif in the linker adopts different structures in RXFP1 and RXFP2.•These differences lead to distinct mechanisms for relaxin-induced activation. Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signaling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa module, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa module, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa module, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2021.167217