期刊
ACS CHEMICAL BIOLOGY
卷 15, 期 12, 页码 3275-3284出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.0c00867
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资金
- National Key Research and Development Program of China [2018YFA0507000]
- National Natural Science Foundation of China [31971362, 81730099, 81861128023]
- National Science and Technology Major Projects for New Drug Development [2018ZX0971100-2-002-013]
- ShanghaiTech University
The GPR52, a class A orphan G protein-coupled receptor (GPCR), is regarded as a promising therapeutic target for the treatment of Huntington's disease and multiple psychiatric disorders. Although the recently solved structure of GPR52 has revealed a binding mechanism likely shared by all reported agonists, the small molecule antagonist E7 cannot fit into this agonist-binding pocket, and its interaction mode with the receptor remains unknown. Here, we employed targeted proteomics and affinity mass spectrometry approaches to uncover a unique binding mode of E7 which acts as a covalent and allosteric ligand of GPR52. Among three Cys residues identified in this study to form covalent conjugates with E7, the intracellular C1564.40 makes the most significant contribution to the antagonism activity of E7. Discovery of this novel intracellular site for covalent attachment of an antagonist would facilitate the design of GPR52-selective negative allosteric modulators which could serve as potential therapeutics for treating Huntington's disease.
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