揭示神经调节素受体激活路径，发现隐藏变构位点，助力戒毒药物研发。
Deciphering the unique dynamic activation pathway in a G protein-coupled receptor enables unveiling biased signaling and identifying cryptic allosteric sites in conformational intermediates
- 结合模拟与实验，解析受体激活的动态渐进机制。
- 发现中间态中存在一个隐蔽的胞内变构位点。
- 为开发新型靶向药物提供原子级理论支持，适合药理与结构生物学研究者。
神经调节素受体1（NTSR1）属于A类G蛋白偶联受体，参与调控多巴胺能神经元活性并产生非阿片类镇痛作用。研究表明，促进NTSR1的β-arrestin偏向性信号传导可能减少毒品滥用行为，为治疗成瘾相关疾病提供新途径。本研究采用基于弹性带的分子动力学模拟、马尔可夫状态模型、时间通信网络分析、定点突变及构象生物传感器等方法，揭示了NTSR1激活的动态逐步转变机制及其信号传递网络。研究还阐明了其独特极性网络、非保守离子锁和芳香簇之间的复杂相互作用。此外，识别出位于受体胞内区的一个隐蔽变构位点，该位点存在于激活路径的中间态。这些发现深化了对NTSR1激活与偏向性信号传导的原子级理解，为开发靶向NTSR1的变构调节剂提供了潜在策略，具有重要的受体生物学、生物物理与医学价值。
原文摘要 · Abstract (English)
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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