Zhang Yue, Zheng Qingchuan, Warshel Arieh, Bai Chen
School of Chemistry and Environmental Engineering, Changchun University of Science and Technology, Changchun 130012, China.
Warshel Institute for Computational Biology, School of Life and Health Sciences, School of Medicine, The Chinese University of Hong Kong (Shenzhen), Shenzhen 518172, China.
J Am Chem Soc. 2025 Jan 29;147(4):3539-3552. doi: 10.1021/jacs.4c15025. Epub 2025 Jan 13.
The parathyroid hormone type 1 receptor (PTH1R) plays a crucial role in modulating various physiological functions and is considered an effective therapeutic target for osteoporosis. However, a lack of detailed molecular and energetic information about PTH1R limits our comprehensive understanding of its activation process. In this study, we performed computational simulations to explore key events in the activation process, such as conformational changes in PTH1R, Gs protein coupling, and the release of guanosine diphosphate (GDP). Our analysis identified kinetic information, including the rate-determining step, transition state, and energy barriers. Free-energy and structural analyses revealed that GDP could be released from the Gs protein when the binding cavity is partially open. Additionally, we predicted important residues, including potential pathogenic mutations, and verified their significance through site-directed mutations. These findings enhance our understanding of class B GPCR activation mechanisms. Furthermore, the methodology employed in this study can be applied to other biophysical systems.
1型甲状旁腺激素受体（PTH1R）在调节多种生理功能中起关键作用，被认为是骨质疏松症的有效治疗靶点。然而，缺乏关于PTH1R的详细分子和能量信息限制了我们对其激活过程的全面理解。在本研究中，我们进行了计算模拟，以探索激活过程中的关键事件，如PTH1R的构象变化、Gs蛋白偶联以及二磷酸鸟苷（GDP）的释放。我们的分析确定了动力学信息，包括速率决定步骤、过渡态和能量屏障。自由能和结构分析表明，当结合腔部分打开时，GDP可以从Gs蛋白中释放出来。此外，我们预测了重要残基，包括潜在的致病突变，并通过定点突变验证了它们的重要性。这些发现加深了我们对B类G蛋白偶联受体激活机制的理解。此外，本研究中采用的方法可应用于其他生物物理系统。
