Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

Yuki Shiimura, Shoichiro Horita, Akie Hamamoto, Hidetsugu Asada, Kunio Hirata, Misuzu Tanaka, Kenji Mori, Tomoko Uemura, Takuya Kobayashi, So Iwata () and Masayasu Kojima ()
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Yuki Shiimura: Kurume University
Shoichiro Horita: Kyoto University
Akie Hamamoto: Kurume University
Hidetsugu Asada: Kyoto University
Kunio Hirata: RIKEN
Misuzu Tanaka: Kurume University
Kenji Mori: National Cerebral and Cardiovascular Center Research Institute
Tomoko Uemura: Kyoto University
Takuya Kobayashi: Kyoto University
So Iwata: Kyoto University
Masayasu Kojima: Kurume University

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Ghrelin is a gastric peptide hormone with important physiological functions. The unique feature of ghrelin is its Serine 3 acyl-modification, which is essential for ghrelin’s activity. However, it remains to be elucidated why the acyl-modification of ghrelin is necessary for activity. To address these questions, we solved the crystal structure of the ghrelin receptor bound to antagonist. The ligand-binding pocket of the ghrelin receptor is bifurcated by a salt bridge between E124 and R283. A striking feature of the ligand-binding pocket of the ghrelin receptor is a wide gap (crevasse) between the TM6 and TM7 bundles that is rich in hydrophobic amino acids, including a cluster of phenylalanine residues. Mutagenesis analyses suggest that the interaction between the gap structure and the acyl acid moiety of ghrelin may participate in transforming the ghrelin receptor into an active conformation.

Date: 2020
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DOI: 10.1038/s41467-020-17554-1

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