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 Å and 3.24 Å, 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.
摘要：
生长抑素受体5(SSTR5)在分泌ACTH的垂体腺瘤中高表达,是治疗库欣病的重要药物靶点。两种环状SST类似物肽(帕瑞肽和奥曲肽)都可以激活SSTR5和SSTR2。帕瑞肽比奥曲肽优先结合SSTR5，而奥曲肽偏向于SSTR2而不是SSTR5。帕瑞肽和奥曲肽缺乏选择性会导致副作用，如高血糖症，胃肠紊乱,和异常的葡萄糖稳态。然而,对于帕瑞肽和奥曲肽与SSTR5的结合和选择性机制知之甚少,这限制了特异性靶向SSTR5的亚型选择性SST类似物药物的开发.这里,我们报告了两种由帕瑞肽和奥曲itde激活的SSTR5-Gi复合物的低温电子显微镜（cryo-EM）结构，分辨率分别为3.09和3.24，分别。结合结构分析和功能实验,我们的结果揭示了配体识别和受体激活的分子机制。我们还证明了帕瑞肽通过帕瑞肽的Tyr(Bzl)/DTrp与SSTR5之间的相互作用优先结合SSTR5。此外，我们发现SSTR2的Q2.63，N6.55，F7.35和ECL2在SSTR2的奥曲肽偏向结合中起关键作用。我们的结果将提供结构见解，并为靶向特定SSTR亚型的更好选择性药物的药物发现提供新的机会。
