Cryo-EM Structures Reveal Distinct Activation Mechanisms for Protein and Small-Molecule RXFP1 Agonists
Researchers used cryo-electron microscopy to determine three structures of the RXFP1 receptor, showing that the native protein agonist relaxin-2 and the small-molecule drug candidate AZD5462 activate the receptor through fundamentally different mechanisms. Relaxin-2 engages the receptor's ectodomain and reorganizes the linker domain into a helical structure, while AZD5462 binds within the transmembrane domain and stabilizes a unique active conformation. These findings provide a structural framework for developing next-generation therapeutics targeting RXFP1 for fibrosis and heart failure treatment.
Scientists have elucidated the structural basis for how two different classes of agonists activate RXFP1, an unusual G protein-coupled receptor involved in pregnancy-related physiological changes and a target for treating fibrosis and heart failure. Using cryo-electron microscopy, the team determined three structures: the ligand-free receptor, the receptor bound to relaxin-2 (the native protein agonist), and the receptor bound to AZD5462 (a small-molecule drug candidate currently in mid-stage clinical trials). The structures reveal that relaxin-2 and AZD5462 employ divergent activation strategies: relaxin-2 binds to the ectodomain and induces conformational reorganization of the linker domain into a helical secondary structure, while AZD5462 binds within the transmembrane domain and stabilizes a distinct active conformation capable of recruiting beta-arrestin. These mechanisms differ from the well-characterized "push-pull" activation model seen in related glycoprotein hormone receptors, suggesting RXFP1 represents a unique activation paradigm.
What's missing
The study does not discuss the functional consequences or therapeutic implications of the divergent activation mechanisms (e.g., whether one mechanism may be preferable for specific disease indications), nor does it address potential off-target effects or selectivity considerations for AZD5462 relative to other receptors.
What different sources said
- bioRxivCenter
Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists
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