Dynamic activation of a GPCR G protein–coupled receptors (GPCRs) coordinate a complex information flow between the outside and inside of a cell. An increasing number of GPCR structures provide insight into function. However, the dynamics that link extracellular sensing to intracellular signaling are not completely understood, because GPCRs used in structure determination are generally modified to constrain their dynamics. Josephs et al. succeeded in determining the structures of an unmodified calcitonin gene–related peptide receptor, which is implicated in migraines, both alone and bound to its neuropeptide ligand. Based on the structures and data from complementary biophysical techniques, they show that initial binding of the peptide causes only minor conformational changes of the GPCR, but dynamically causes changes at the intracellular side that facilitate G protein binding and activation. Science , this issue p. eabf7258