中国科学技术大学田长麟团队开发出生长抑素受体3配体识别和激活的结构和动力学研究。2026年2月11日，国际知名学术期刊《中国药理学报》发表了这一成果。

研究组报道了分辨率达2.90 Å的人源SSTR3-Gi蛋白复合物与奥曲肽结合的冷冻电镜结构。它们的结构揭示了配体识别和受体激活的分子机制。

此外，诱变分析表明，残基R203^5·35SSTR3和F294^7·35在介导奥曲肽亚型选择性中发挥关键作用。利用电子顺磁共振波谱技术研究了SSTR3的构象动力学。他们的研究结果表明，在配体结合或G蛋白偶联过程中，SSTR3的跨膜螺旋6 （TM6）上的标记位点逐渐暴露于细胞外环境，并表现出增加的动力学特性。他们的工作提供了结构和动态的见解，将促进针对SSTR的亚型选择性药物的合理设计，并具有改进的治疗概况。

据悉，生长抑素受体3 （Somatostatin receptor 3, SSTR3）具有负调控激素释放和细胞增殖等重要生物学功能，是治疗内分泌疾病和无功能垂体肿瘤的重要靶点。然而，由于缺乏对SSTR3配体识别和构象动力学的分子理解，开发更有效和更安全的生长抑素能疗法受到限制。

附：英文原文

Title: Structural and dynamic insights into ligand recognition and activation of somatostatin receptor 3

Author: Chen, Xue, Guo, Sen, Li, Ying-ge, Liu, Ao-kun, Kuang, Jian, Shi, Pan, Yu, Lu, Yang, Fan, Tian, Chang-lin

Issue&Volume: 2026-02-11

Abstract: Somatostatin receptor 3 (SSTR3) exerts critical biological functions such as negatively regulating hormone release and cell proliferation, making it a promising therapeutic target for endocrine disorders and nonfunctioning pituitary tumors. However, the development of more effective and safer somatostatinergic therapies is limited due to a lack of molecular understanding of the ligand recognition and conformational dynamics of SSTR3. Here, we report the cryo-EM structure of the human SSTR3-Gi complex bound to octreotide at 2.90 resolution. Our structures reveal the molecular mechanisms of ligand recognition and receptor activation. Furthermore, mutagenesis analyses reveal that residue R203·3 of SSTR3 and F294·3 of SSTR2 play critical roles in mediating the subtype selectivity of octreotide. Using electron paramagnetic resonance spectroscopy, we have investigated the conformational dynamics of SSTR3. Our findings demonstrate that during ligand binding or G protein coupling, the labeled site on transmembrane helix 6 (TM6) of SSTR3 progressively becomes exposed to the extracellular environment and exhibits increased dynamical characteristics. Our work provides structural and dynamic insights that will facilitate the rational design of subtype-selective drugs targeting SSTRs and possessing improved therapeutic profiles.

DOI: 10.1038/s41401-025-01740-2

Source:https://www.nature.com/articles/s41401-025-01740-2