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arXiv · 2504.17624

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

Jigang Fan·Chunhao Zhu·Xiaobing Lan·Haiming Zhuang·Mingyu Li·Jian Zhang·Shaoyong Lu
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Abstract

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.

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Jigang Fan, Chunhao Zhu, Xiaobing Lan, Haiming Zhuang, Mingyu Li, Jian Zhang, Shaoyong Lu. 2025-04-24. Deciphering the unique dynamic activation pathway in a G protein-coupled receptor enables unveiling biased signaling and identifying cryptic allosteric sites in conformational intermediates. https://arxiv.org/abs/2504.17624

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