Cryo-EM complex structure of active GPR75 with a nanobody

Although there has been enormous progress in the last half-century in the drug discovery targeting obesity and associated co-morbidities, the clinical treatment of obesity remains tremendously challenging. GPR75 is an orphan receptor and is suggested to be a potential novel target for the control of...

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Bibliographic Details
Published inbioRxiv
Main Authors Lv, Zilin, He, Yuntong, Xiang, Yuning, Li, Jing, Meng, Fanhao, Zhao, Huimin, Guo, Hanbo, He, Dong, Wang, Yanxia, Wei, Zhuo, Liu, Yujie, Ni, Xiaodan, Heng, Jie
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 18.08.2022
Subjects
Allosteric properties
Drug discovery
Metabolic disorders
Nanobodies
Obesity
Receptor mechanisms
Signal transduction
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Summary:Although there has been enormous progress in the last half-century in the drug discovery targeting obesity and associated co-morbidities, the clinical treatment of obesity remains tremendously challenging. GPR75 is an orphan receptor and is suggested to be a potential novel target for the control of obesity and related metabolic disorders. Inhibition of the GPR75 signaling pathway by small molecules, antibodies, or genetic manipulations may provide a therapeutic strategy for obesity. Here, we report the active-like Cryo-EM structure of human GPR75 with an intracellular nanobody, which reveals the receptor activation mechanism. The extensive interaction network required to achieve the active structure helps explain the allosteric coupling between the orthosteric pocket and the G-protein coupling domain. The well-defined orthosteric ligand binding pocket of human GPR75 provides a structural basis for anti-obesity drug discovery. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.08.18.503988