Significance G protein-coupled receptor (GPCR) structures determined by X-ray crystallography or cryo-electron microscopy include 28 receptors for which complexes with agonists and antagonists can be compared. In all these comparisons, an interatomic distance representing the size of the orthosteric ligand binding groove differs by less than 2.9 Å. In this report, ¹⁹ F-NMR observations of the NK1R-bound drug molecule aprepitant show that the orthosteric binding groove undergoes transient fluctuations with amplitudes 6 to 8 Å. We propose that this large-amplitude plasticity enables a multistep selection of functional ligands with variable efficacies. These insights into structural dynamics also provide a rationale for the observation that diffracting crystals are obtained for GPCR complexes with only few of the ligands that bind to the receptors.