PT  - JOURNAL ARTICLE
AU  - Yue Wang
AU  - Shimeng Guo
AU  - Youwen Zhuang
AU  - Ying Yun
AU  - Peiyu Xu
AU  - Xinheng He
AU  - Jia Guo
AU  - Wanchao Yin
AU  - H. Eric Xu
AU  - Xin Xie
AU  - Yi Jiang
TI  - Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor
AID  - 10.1101/2021.06.09.447478
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.09.447478
4099  - http://biorxiv.org/content/early/2021/06/10/2021.06.09.447478.short
4100  - http://biorxiv.org/content/early/2021/06/10/2021.06.09.447478.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.