Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors.

生长抑素受体 2 (SSTR2) 在神经内分泌肿瘤中高度表达，并代表治疗靶点。几种模拟内源性配体生长抑素的肽类似物可用于临床，但部分患者的治疗效果较差，这可能与亚型选择性或细胞表面表达有关。在这里，我们通过评估第一代多肽药物奥曲肽和新一代小分子帕妥索汀的药理特性，阐明了它们的信号偏倚特征。然后，我们对 SSTR2-Gi 复合物进行冷冻电子显微镜分析，以确定药物如何以选择性方式激活 SSTR2。在这项工作中，我们破译了 SSTR2 感应奥曲肽和帕妥索汀的配体识别机制、亚型选择性和信号偏置特性，