Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists
Abstract
RXFP1 is an unusual G protein-coupled receptor (GPCR) that mediates physiological adaptations to pregnancy and is a therapeutic target due to its benefits in treatment of fibrosis and heart failure. Protein and small-molecule agonists are currently in mid-stage clinical trials. Here, we present three cryo-electron microscopy structures of RXFP1: ligand-free, bound to the native agonist relaxin-2, and bound to the small-molecule drug candidate AZD5462. These structures show that relaxin-2 engages the receptor's ectodomain while AZD5462 binds within transmembrane domain. Together with hydrogen-deuterium exchange mass spectrometry, we show that relaxin-2 induces conformational reorganization of the linker domain into a helical secondary structure. In contrast, AZD5462 stabilizes a unique active conformation capable of inducing β-arrestin recruitment. Both mechanisms are distinctive from the "push-pull" mechanism of glycoprotein hormone receptors. Altogether, our findings define divergent activation mechanisms for protein and small-molecule agonists of RXFP1 and provide structural framework for next-generation drug discovery targeting relaxin receptors and their relatives.
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BibTeX
@misc{oseiowusu2026divergent,
title = {{Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists}},
author = {James Osei-Owusu and Tristan Girbau and Xunan Wang and Jeffrey S Smith and Pengxiang Shen and Sarah C Erlandson and Amanda K Williamson and Xiaojing Cong and Mark W Grinstaff and Daniel E Kahne and Cherine Bechara and Andrew C Kruse},
howpublished = {HAL},
year = {2026},
month = jun,
doi = {10.64898/2026.06.10.731386},
url = {https://hal.science/hal-05757595v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists
AU - James Osei-Owusu
AU - Tristan Girbau
AU - Xunan Wang
AU - Jeffrey S Smith
AU - Pengxiang Shen
AU - Sarah C Erlandson
AU - Amanda K Williamson
AU - Xiaojing Cong
AU - Mark W Grinstaff
AU - Daniel E Kahne
AU - Cherine Bechara
AU - Andrew C Kruse
PY - 2026
DA - 2026/06/11
PB - HAL
DO - 10.64898/2026.06.10.731386
UR - https://hal.science/hal-05757595v1
AB - RXFP1 is an unusual G protein-coupled receptor (GPCR) that mediates physiological adaptations to pregnancy and is a therapeutic target due to its benefits in treatment of fibrosis and heart failure. Protein and small-molecule agonists are currently in mid-stage clinical trials. Here, we present three cryo-electron microscopy structures of RXFP1: ligand-free, bound to the native agonist relaxin-2, and bound to the small-molecule drug candidate AZD5462. These structures show that relaxin-2 engages the receptor's ectodomain while AZD5462 binds within transmembrane domain. Together with hydrogen-deuterium exchange mass spectrometry, we show that relaxin-2 induces conformational reorganization of the linker domain into a helical secondary structure. In contrast, AZD5462 stabilizes a unique active conformation capable of inducing β-arrestin recruitment. Both mechanisms are distinctive from the "push-pull" mechanism of glycoprotein hormone receptors. Altogether, our findings define divergent activation mechanisms for protein and small-molecule agonists of RXFP1 and provide structural framework for next-generation drug discovery targeting relaxin receptors and their relatives.
ER -