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Cited by 18Receptor Mechanisms and SignalingPregnancy-related medical researchNeuropeptides and Animal Physiology

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

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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.·2021·Journal of Molecular Biology
DOI 10.1016/j.jmb.2021.167217

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Abstract

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.

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Metadata

Authors
Sethi, A., Bruell, S., Ryan, T., Yan, F., Tanipour, M. H., Mok, Y.-F., Draper-Joyce, C., Khandokar, Y., Metcalfe, R. D., Griffin, M. D. W., Scott, D. J., Hossain, M. A., Petrie, E. J., Bathgate, R. A. D., & Gooley, P. R.
Affiliations
  • The University of Melbourne (AU)
  • Australian Nuclear Science and Technology Organisation (AU)
Corresponding author
  • Bathgate, Ross A.D.
  • Gooley, Paul R.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2021-10
Volume
433
Issue
21
Pages
167217
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2021.167217
OpenAlex
W3197618578
Cited by
18
References
1
Citations by year
2026: 4 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 1
FWCI
0.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • State Government of Victoria
  • Australian Nuclear Science and Technology Organisation
  • National Health and Medical Research Council (1042650, 1100676)
  • University of Melbourne
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy-related medical research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
relaxin, RXFP1, RXFP2, relaxin receptor, G protein-coupled receptor activation, tethered agonist, receptor ectodomain
MeSH terms
Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Binding Sites, Gene Expression Regulation, Genetic Vectors, Humans, Kinetics, Models, Molecular, Protein Binding, Recombinant Proteins, Relaxin, Signal Transduction, Receptors, Peptide, Nuclear Magnetic Resonance, Biomolecular, Amino Acid Motifs, Receptors, G-Protein-Coupled, Protein Interaction Domains and Motifs, HEK293 Cells

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