Exploring the constitutive activation mechanism of the class A orphan GPR20.

Autor: Zhang MY; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.; Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Ao JY; Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.; Institute of Hepatobiliary and Pancreatic Surgery, Tongji University School of Medicine, Shanghai, 200120, China., Liu N; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China., Chen T; Department of Cardiology, Changzheng Hospital, Affiliated to Naval Medical University, Shanghai, 200003, China. pipidan@126.com., Lu SY; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China. lushaoyong@sjtu.edu.cn.; Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. lushaoyong@sjtu.edu.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Sep 10. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1038/s41401-024-01385-7
Abstrakt: 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 G i . 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 G i 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.
(© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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