宁夏医科大学Shao-yong Lu等研究人员合作揭示A类孤儿受体GPR20的组成性激活机制。相关论文于2024年9月10日在线发表在《中国药理学报》杂志上。

研究人员表示，GPR20是一种孤儿GPCR，在肠道组织中表现出显著表达，并被视为治疗胃肠道间质瘤的潜在治疗靶点。GPR20在与G_i偶联时表现出高度的组成性活性。尽管GPCR组成性激活在药理学上具有重要意义，但其机制长期未明。

附：英文原文

Title: Exploring the constitutive activation mechanism of the class A orphan GPR20

Author: Zhang, Ming-yang, Ao, Jian-yang, Liu, Ning, Chen, Ting, Lu, Shao-yong

Issue&Volume: 2024-09-10

Abstract: GPR20, an orphan G protein-coupled receptor (GPCR), shows significant expression in intestinal tissue and represents a potential therapeutic target to treat gastrointestinal stromal tumors. GPR20 performs high constitutive activity when coupling with Gi. Despite the pharmacological importance of GPCR constitutive activation, determining the mechanism has long remained unclear. In this study, we explored the constitutive activation mechanism of GPR20 through large-scale unbiased molecular dynamics simulations. Our results unveil the allosteric nature of constitutively activated GPCR signal transduction involving extracellular and intracellular domains. Moreover, the constitutively active state of the GPR20 requires both the N-terminal cap and Gi protein. The N-terminal cap of GPR20 functions like an agonist and mediates long-range activated conformational shift. Together with the previous study, this study enhances our knowledge of the self-activation mechanism of the orphan receptor, facilitates the drug discovery efforts that target GPR20.

DOI: 10.1038/s41401-024-01385-7

Source: https://www.nature.com/articles/s41401-024-01385-7