中国科学技术大学杨帆等合作近期取得重要工作进展，他们对生长抑素受体5（SSTR5）与环肽结合的结构进行了解析相关研究成果2024年6月26日在线发表于《中国药理学报》杂志上。

据介绍，SSTR5在分泌ACTH的垂体腺瘤中高度表达，是治疗库欣病的重要药物靶点。两种环状SST类似肽（帕西肽和奥曲肽）均能激活SSTR5和SSTR2。帕西肽比奥曲肽优先结合SSTR5，而奥曲肽比SSTR5更倾向于结合SSTR2。帕西肽和奥曲肽缺乏选择性会导致副作用，如高血糖、胃肠道紊乱和葡萄糖稳态异常。然而，对帕西肽和奥曲肽与SSTR5的结合和选择性机制知之甚少，限制了特异性靶向SSTR5亚型选择性SST类似物药物的开发。

研究人员报道了帕西肽和奥曲肽分别以3.09Å和3.24Å的分辨率激活的SSTR5-Gi复合物的两种冷冻电镜（cryo-EM）结构。结合结构分析和功能实验，研究人员揭示了配体识别和受体激活的分子机制。帕西肽通过Tyr（Bzl）/^DTrp和SSTR5之间的相互作用优先结合SSTR5。

此外，研究人员发现SSTR2的Q^2.63、N^6.55、F^7.35和ECL2在奥曲肽偏向性结合SSTR2中起着至关重要的作用。

总之，这一研究结果将提供结构见解，并为针对特定SSTR亚型的更好选择性药物开发提供新的机会。

附：英文原文

Title: Structural insights into somatostatin receptor 5 bound with cyclic peptides

Author: Li, Ying-ge, Meng, Xian-yu, Yang, Xiru, Ling, Sheng-long, Shi, Pan, Tian, Chang-lin, Yang, Fan

Issue&Volume: 2024-06-26

Abstract: Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing’s disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 and 3.24, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/DTrp of pasireotide and SSTR5. Moreover, we find that the Q2.63, N6.55, F7.35 and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.

DOI: 10.1038/s41401-024-01314-8

Source: https://www.nature.com/articles/s41401-024-01314-8