Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor

Yue Wang, Shimeng Guo, Youwen Zhuang, Ying Yun, Peiyu Xu, Xinheng He, Jia Guo, Wanchao Yin, H. Eric Xu (), Xin Xie () and Yi Jiang ()
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Yue Wang: Chinese Academy of Sciences
Shimeng Guo: Nanjing University of Chinese Medicine
Youwen Zhuang: Chinese Academy of Sciences
Ying Yun: University of Chinese Academy of Sciences
Peiyu Xu: Chinese Academy of Sciences
Xinheng He: Chinese Academy of Sciences
Jia Guo: Chinese Academy of Sciences
Wanchao Yin: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Xin Xie: University of Chinese Academy of Sciences
Yi Jiang: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Ghrelin, also called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.

Date: 2021
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DOI: 10.1038/s41467-021-25364-2

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