Somatostatin receptors (SSTRs) are widely distributed throughout the human body and play crucial roles in various physiological processes. They are recognized as key targets for both radiotherapy and radiodiagnosis due to their overexpression in several cancer types. However, the discovery and design of selective drugs for each of the five isoforms have been significantly hindered by the lack of complete structural information. In this study, we conducted a systematic computational analysis of all five SSTRs in complex with the endogenous ligand somatostatin to elucidate their structural and dynamic features. We thoroughly characterized each isoform using available experimental structures for SSTR2 and SSTR4, as well as AlphaFold2 models for SSTR1, SSTR3, and SSTR5. By performing multi-copy μs-long molecular dynamics simulations, we examined the differences and similarities in dynamical behavior and somatostatin binding among all SSTRs. Our analysis focused on understanding the opening and closing movements of the extracellular loop 2, which are crucial for ligand binding and recognition. Interestingly, we observed a unique conformation of somatostatin within the binding pocket of SSTR5 in which the loop can partially close, as compared to the other isoforms. Fingerprint analyses provided distinct interaction patterns of somatostatin with all receptors, thus enabling precise guidelines for the discovery and development of more selective somatostatin-based pharmaceuticals tailored for precision medicine therapies.

中文翻译：

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通过分子动力学模拟探索生长抑素受体选择性的关键特征

生长抑素受体（SSTR）广泛分布于人体各处，在各种生理过程中发挥着至关重要的作用。由于它们在多种癌症类型中过度表达，因此被认为是放射治疗和放射诊断的关键靶点。然而，由于缺乏完整的结构信息，五种异构体的选择性药物的发现和设计受到了严重阻碍。在这项研究中，我们对所有五种 SSTR 与内源性配体生长抑素的复合物进行了系统的计算分析，以阐明它们的结构和动态特征。我们使用 SSTR2 和 SSTR4 的可用实验结构以及 SSTR1、SSTR3 和 SSTR5 的 AlphaFold2 模型彻底表征了每种亚型。通过进行多拷贝μs长分子动力学模拟，我们检查了所有SSTR之间动力学行为和生长抑素结合的差异和相似性。我们的分析重点是了解细胞外环 2 的打开和关闭运动，这对于配体结合和识别至关重要。有趣的是，我们在 SSTR5 的结合口袋内观察到生长抑素的独特构象，与其他亚型相比，其中环可以部分闭合。指纹分析提供了生长抑素与所有受体的独特相互作用模式，从而为发现和开发针对精准医学治疗量身定制的更具选择性的生长抑素药物提供了精确的指导。