Cryo-EM Structures Reveal Distinct Activation Mechanisms for Protein and Small-Molecule RXFP1 Agonists
Researchers have determined three cryo-electron microscopy structures of the RXFP1 relaxin receptor — in its unbound state, bound to the natural hormone relaxin-2, and bound to the small-molecule drug candidate AZD5462 — revealing that the two agonists activate the receptor through fundamentally different mechanisms. RXFP1 is a G protein-coupled receptor involved in pregnancy adaptations and is being investigated as a therapeutic target for fibrosis and heart failure, with both protein and small-molecule agonists currently in mid-stage clinical trials. Understanding these divergent activation pathways provides a structural blueprint that could guide the design of more effective next-generation drugs targeting RXFP1 and related receptors.
A new structural biology study published on bioRxiv presents three cryo-electron microscopy (cryo-EM) structures of RXFP1, an atypical G protein-coupled receptor (GPCR) that plays a key role in physiological adaptations during pregnancy and represents a promising drug target for fibrosis and heart failure. The structures capture RXFP1 in its ligand-free state, bound to its native agonist relaxin-2, and bound to the investigational small-molecule drug AZD5462. The researchers found that relaxin-2 binds to the receptor's extracellular ectodomain and triggers a conformational reorganization of a linker domain into a helical secondary structure, a finding supported by hydrogen-deuterium exchange mass spectrometry. AZD5462, by contrast, binds within the transmembrane domain and stabilizes a distinct active conformation that promotes beta-arrestin recruitment, a signaling pathway with different downstream effects. Critically, both mechanisms differ from the previously characterized 'push-pull' activation mechanism seen in the related glycoprotein hormone receptors. The authors argue that these findings define two divergent activation mechanisms for RXFP1 and establish a structural framework that could inform the rational design of next-generation therapeutics targeting relaxin receptors.
What's missing
As a preprint, this study has not yet undergone formal peer review, and the functional consequences of the two divergent activation mechanisms — particularly whether beta-arrestin-biased signaling via AZD5462 translates to meaningfully different therapeutic or side-effect profiles compared to relaxin-2 — are not fully characterized. The study does not report clinical efficacy or safety data for AZD5462, and the structural findings await independent validation.
What different sources said
- bioRxivCenter
Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists
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