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Neurotensin receptor 1 (NTSR1), a member of the Class A G protein-coupledreceptor superfamily, plays an important role in modulating dopaminergicneuronal activity and eliciting opioid-independent analgesia. Recent studiessuggest that promoting \{beta}-arrestin-biased signaling in NTSR1 may diminishdrugs of abuse, such as psychostimulants, thereby offering a potential avenuefor treating human addiction-related disorders. In this study, we utilized anovel computational and experimental approach that combined nudged elasticband-based molecular dynamics simulations, Markov state models, temporalcommunication network analysis, site-directed mutagenesis, and conformationalbiosensors, to explore the intricate mechanisms underlying NTSR1 activation andbiased signaling. Our study reveals a dynamic stepwise transition mechanism andactivated transmission network associated with NTSR1 activation. It also yieldsvaluable insights into the complex interplay between the unique polar network,non-conserved ion locks, and aromatic clusters in NTSR1 signaling. Moreover, weidentified a cryptic allosteric site located in the intracellular region of thereceptor that exists in an intermediate state within the activation pathway.Collectively, these findings contribute to a more profound understanding ofNTSR1 activation and biased signaling at the atomic level, thereby providing apotential strategy for the development of NTSR1 allosteric modulators in therealm of G protein-coupled receptor biology, biophysics, and medicine.

Deciphering the unique dynamic activation pathway in a G protein-coupled  receptor enables unveiling biased signaling and identifying cryptic  allosteric sites in conformational intermediates