Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by 'Driver Chemical Groups' of Modulators: A Comparative Molecular Dynamics Simulation.

Small-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulation, highlighting the significance of deciphering the internal fine-tuning mechanism. Here, we conducted a synergistic application of a Gaussian accelerated molecular dynamics simulation, a conventional molecular dynamics simulation, and Markov state models (MSM) to investigate the underlying mechanism of 'driver chemical groups' of modulators triggering inverse signaling. The results indicated that the flexibility of the leucine moiety in NTSR1 agonists contributes to the inward displacement of TM7 through a loosely coupled allosteric pathway, while the rigidity of the adamantane moiety in NTSR1 antagonists leads to unfavorable downward transduction of agonistic signaling. Furthermore, we found that R322, Y319, F353, R148, S356, and S357 may play a key role in inducing the activation of NTSR1. Together, our findings not only highlight the ingenious signal transduction within class A GPCRs but also lay a foundation for the development of targeted drugs harboring different regulatory functions of NTSR1.