探索 A 类孤儿 GPR20 的构成性激活机制

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Acta Pharmacologica Sinica Pub Date : 2024-09-10 DOI:10.1038/s41401-024-01385-7
Ming-yang Zhang, Jian-yang Ao, Ning Liu, Ting Chen, Shao-yong Lu
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引用次数: 0

摘要

GPR20 是一种孤儿 G 蛋白偶联受体(GPCR),在肠道组织中大量表达,是治疗胃肠道间质瘤的潜在治疗靶点。GPR20 与 Gi 偶联时具有很高的组成活性。尽管 GPCR 构成性激活具有重要的药理作用,但其机制长期以来仍不清楚。在这项研究中,我们通过大规模无偏分子动力学模拟探索了 GPR20 的组成型激活机制。我们的结果揭示了组成型激活的 GPCR 信号转导涉及胞外和胞内结构域的异构性质。此外,GPR20 的组成活化状态需要 N 端帽和 Gi 蛋白。GPR20 的 N 端帽具有类似于激动剂的功能,可介导长程活化构象转移。这项研究与之前的研究相结合,增强了我们对孤儿受体自激活机制的认识,促进了以 GPR20 为靶点的药物研发工作。
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Exploring the constitutive activation mechanism of the class A orphan GPR20

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.

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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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