Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode
Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode
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DOI：
10.1038/s41467-020-17554-1
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发表时间：
2020-08-19
影响因子：
16.6
通讯作者：
Kojima, Masayasu
中科院分区：
文献类型：
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作者：
Shiimura, Yuki;Horita, Shoichiro;Kojima, Masayasu
Ghrelin是一种具有重要生理功能的胃肽激素。 ghrelin 的独特之处在于其丝氨酸 3 酰基修饰，这对于 ghrelin 的活性至关重要。然而，为什么胃饥饿素的酰基修饰对于活性是必需的，仍有待阐明。为了解决这些问题，我们解析了与拮抗剂结合的生长素释放肽受体的晶体结构。生长素释放肽受体的配体结合袋通过 E124 和 R283 之间的盐桥分叉。生长素释放肽受体的配体结合袋的一个显着特征是 TM6 和 TM7 束之间的宽间隙（裂缝），富含疏水性氨基酸，包括一簇苯丙氨酸残基。诱变分析表明，间隙结构与生长素释放肽酰基酸部分之间的相互作用可能参与生长素释放肽受体转变为活性构象。生长素释放肽是一种胃肽激素，具有重要的生理功能，包括生长激素释放和食欲刺激活性。在这里，作者解析了与拮抗剂结合的生长素释放肽受体的晶体结构，并提出了酰基修饰的生长素释放肽激活的可能机制。
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. Ghrelin is a gastric peptide hormone with important physiological functions, including growth hormone release and appetite-stimulating activity. Here, authors solved the crystal structure of the ghrelin receptor bound to antagonist and suggested a possible mechanism of activation by acyl-modified ghrelin.