G-protein coupled receptors (GPCRs) are the largest superfamily of membrane receptors that regulate a variety of physiological functions. Given the large size of the family, their physiological importance and being integral membrane proteins, GPCRs are considered attractive targets for treatment of a wide range of conditions from allergic reactions to neurodegenerative diseases. Indeed, 30-40% of marketed drugs target GPCRs. However, the mechanisms governing GPCR activation, which is crucial for development of tailored drugs, are still unknown. The current proposed mechanism underlying GPCR activation, derived mainly from cryo-EM and X-ray crystallography structures and protein dynamics by NMR, EPR and MD simulations, is conformational selection, in which the apo state receptor exists in a conformational pre-equilibrium between different active and inactive states, and the selected conformation by ligand with different efficacies, shifts this equilibrium accordingly. However, conformational selection is insufficient to explain the complex pharmacological behaviour of GPCRs such as distinct receptor responses to chemically divergent agonists and hidden allosteric sites. Here we focused on the mechanism of activation of neurotensin receptor 1 (NTS1), a class A GPCR that plays critical roles in the central nervous system and gastrointestinal tract. NTS1 is activated by the endogenous linear 13-residue peptide neurotensin, NT (pELYENKPRRPYIL). Despite several structures of NTS1 being available, the mechanism underlying NTS1 activation is still unknown. Here, our peptide-observed and receptor-observed 19F-NMR experiments on NTS1 proposed that ligand binding precedes and induces conformational changes in the extracellular vestibule of NTS1. The induced fit mechanism was further confirmed by kinetic analysis of NT binding to NTS1 using stopped-flow fluorescence. Receptor mutagenesis indicated that NT binding promotes receptor lidding by triggering the engagement of the N-terminal of NTS1 with the extracellular loop 2 of the receptor. These results will guide further approaches to drug design.