Exploring the constitutive activation mechanism of the class A orphan GPR20  

作　　者：Ming-yang Zhang Jian-yang Ao Ning Liu Ting Chen Shao-yong Lu 

机构地区：[1]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 [2]Medicinal Chemistry and Bioinformatics Center,Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China [3]Department of Hepatobiliary and Pancreatic Surgery,Shanghai East Hospital,Tongji University School of Medicine,Shanghai,200120,China [4]Institute of Hepatobiliary and Pancreatic Surgery,Tongji University School of Medicine,Shanghai,200120,China [5]Department of Cardiology,Changzheng Hospital,Affiliated to Naval Medical University,Shanghai,200003,China

出　　处：《Acta Pharmacologica Sinica》2025年第2期500-511,共12页中国药理学报(英文版)

基　　金：supported by grants from the National Key R&D Program of China(No.2023YFC3404700);the National Natural Science Foundation of China(No.22077082).

摘　　要：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.

关 键 词：G protein-coupled receptor molecular dynamics simulations allosteric communication conformational shift drug discovery 

分 类 号：O62[理学—有机化学]