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 beta-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.
Osei-Owusu, J., Girbau, T., Wang, X., Smith, J. S., Shen, P., Erlandson, S., Williamson, A., Cong, X., Grinstaff, M., Kahne, D., BECHARA, C., Kruse, A.
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