Guccione C, Gervasoni S, Öztürk I, Bosin A, Ruggerone P, Malloci G
Department of Physics, University of Cagliari, Monserrato (Cagliari), 09042, Italy.
Comput Struct Biotechnol J. 2024 Mar 18;23:1311-1319. doi: 10.1016/j.csbj.2024.03.005. eCollection 2024 Dec.
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.
生长抑素受体（SSTRs）广泛分布于人体全身，在各种生理过程中发挥着关键作用。由于它们在几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，针对五种亚型中每一种的选择性药物的发现和设计受到了显著阻碍。在本研究中，我们对与内源性配体生长抑素结合的所有五种SSTRs进行了系统的计算分析，以阐明它们的结构和动力学特征。我们利用SSTR2和SSTR4的现有实验结构以及SSTR1、SSTR3和SSTR5的AlphaFold2模型对每种亚型进行了全面表征。通过进行多拷贝微秒级长时间分子动力学模拟，我们研究了所有SSTRs在动力学行为和生长抑素结合方面的差异和相似性。我们的分析重点是了解细胞外环2的开闭运动，这对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一种独特构象，与其他亚型相比，该环可以部分关闭。指纹分析提供了生长抑素与所有受体的不同相互作用模式，从而为发现和开发更具选择性的基于生长抑素的药物提供了精确指导，这些药物适用于精准医学治疗。
