香港中文大学(深圳)白晨研究团队揭示了决定人甲状旁腺激素1型受体激活过程的关键相互作用改变。相关研究成果发表在2025年1月13日出版的《美国化学会杂志》。

甲状旁腺激素1型受体（PTH1R）在调节各种生理功能中起着至关重要的作用，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人们对其活化过程的全面理解。

该文中，研究人员通过计算模拟探索激活过程中的关键事件，如PTH1R的构象变化、Gs蛋白偶联和鸟苷二磷酸（GDP）的释放。研究分析确定了动力学信息，包括速率决定步骤、过渡态和能量势垒。自由能和结构分析表明，当结合腔部分打开时，Gs蛋白可以释放GDP。

此外，研究预测了重要的残基，包括潜在的致病突变，并通过定点突变验证了它们的意义。这些发现加深了研究人员对B类GPCR激活机制的理解。此外，该研究中采用的方法可以应用于其他生物物理系统。

附：英文原文

Title: Key Interaction Changes Determine the Activation Process of Human Parathyroid Hormone Type 1 Receptor

Author: Yue Zhang, Qingchuan Zheng, Arieh Warshel, Chen Bai

Issue&Volume: January 13, 2025

Abstract: 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.

DOI: 10.1021/jacs.4c15025

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c15025