Deciphering the unique dynamic activation pathway in a G protein-coupled receptor enables unveiling biased signaling and identifying cryptic allosteric sites in conformational intermediates
Fuente:
arXiv
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Preprint |
| Published: |
2025
|
| Subjects: | |
| Online Access: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1866909592287444992 |
|---|---|
| author | Fan, Jigang Zhu, Chunhao Lan, Xiaobing Zhuang, Haiming Li, Mingyu Zhang, Jian Lu, Shaoyong |
| author_facet | Fan, Jigang Zhu, Chunhao Lan, Xiaobing Zhuang, Haiming Li, Mingyu Zhang, Jian Lu, Shaoyong |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2504_17624 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Deciphering the unique dynamic activation pathway in a G protein-coupled receptor enables unveiling biased signaling and identifying cryptic allosteric sites in conformational intermediates Fan, Jigang Zhu, Chunhao Lan, Xiaobing Zhuang, Haiming Li, Mingyu Zhang, Jian Lu, Shaoyong Biomolecules Artificial Intelligence 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. |
| title | Deciphering the unique dynamic activation pathway in a G protein-coupled receptor enables unveiling biased signaling and identifying cryptic allosteric sites in conformational intermediates |
| topic | Biomolecules Artificial Intelligence |
| url | https://arxiv.org/abs/2504.17624 |