2025/04/24 by Jigang Fan, Chunhao Zhu, Fan, Jigang +11
Biochemistry, Genetics and Molecular Biology · #Artificial Intelligence (cs.AI) #Biomolecules (q-bio.BM) #FOS: Biological sciences #FOS: Computer and information sciences #Receptor Mechanisms and Signaling
paper · pdf · doi:10.48550/arxiv.2504.17624
openalex publication_date 2025/04/24 · openalex created_date 2025/10/18 · openalex updated_date 2026/07/28
Neurotensin receptor 1 (NTSR1), a member of the Class A G protein-coupled receptor superfamily, plays an important role in modulating dopaminergic neuronal activity and eliciting opioid-independent analgesia. Recent studies suggest that promoting \beta-arrestin-biased signaling in NTSR1 may diminish drugs of abuse, such as psychostimulants, thereby offering a potential avenue for treating human addiction-related disorders. In this study, we utilized a novel computational and experimental approach that combined nudged elastic band-based molecular dynamics simulations, Markov state models, temporal communication network analysis, site-directed mutagenesis, and conformational biosensors, to explore the intricate mechanisms underlying NTSR1 activation and biased signaling. Our study reveals a dynamic stepwise transition mechanism and activated transmission network associated with NTSR1 activation. It also yields valuable insights into the complex interplay between the unique polar network, non-conserved ion locks, and aromatic clusters in NTSR1 signaling. Moreover, we identified a cryptic allosteric site located in the intracellular region of the receptor that exists in an intermediate state within the activation pathway. Collectively, these findings contribute to a more profound understanding of NTSR1 activation and biased signaling at the atomic level, thereby providing a potential strategy for the development of NTSR1 allosteric modulators in the realm of G protein-coupled receptor biology, biophysics, and medicine.