选择性连接体识别和激活体静止素受体SSTR1和SSTR3
Yujue Wang1,2,3, Youwei Xu4, Yue Wang4
1Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
概括
对体静止素受体 (SSTR) 的结构洞察力揭示了激动剂如何结合,有助于开发针对性治疗内分泌疾病和神经内分泌瘤的向疗法.
科学领域:
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
- 内分泌学 在内分泌学.
背景情况:
- 体静止素受体 (SSTRs) 调节激素释放和细胞增殖,使它们成为内分泌疾病,特别是神经内分泌瘤的关键治疗点.
- 目前的疗法面临的局限性是由于对SSTR亚型联结体相互作用的分子理解不完整.
- 开发选择性SSTR激动剂需要详细了解受体-连接体结合动态.
研究的目的:
- 阐明Gi-合SSTR1和SSTR3激活的分子机制.
- 提供高分辨率的结构洞察力,了解跨SSTR亚型的配体识别和受体激活.
- 建立一个框架来设计具有改善治疗特征的亚型选择性SSTR配体.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定与各种激动剂结合的SSTR1和SSTR3的结构.
- 对四种不同的冷EM结构的分析,包括那些含有化的结构,L-797591和L-796778.
- 变异性研究,以调查特定氨基酸残留在连接体结合和选择性中的作用.
主要成果:
- 在SSTR亚型的扩展结合口袋内揭示了泛agonist pasireotide的保守结合模式.
- 与内源性索马托斯塔丁 (SST14) 和其他已确定的配体相比,确定了不同的结合方式.
- 揭示了SSTR1和SSTR3连接体结合口袋的动态特征以及连接体选择性的关键决定因素.
结论:
- 这项研究为SSTR激活和连接体选择性提供了关键的分子见解.
- 这些发现为合理设计新型,亚型选择性的SSTR配体提供了结构基础.
- 这项工作有助于开发更有效,更安全的SSTR向治疗内分泌疾病的疗法.
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