Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, 7624 Pécs, Hungary.
János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, 7624 Pécs, Hungary.
Int J Mol Sci. 2022 Jun 21;23(13):6878. doi: 10.3390/ijms23136878.
Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin-SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.
生长抑素（也称为生长激素抑制激素或生长激素释放抑制因子）是一种对内分泌系统正常功能、局部炎症反应、情绪和运动协调以及对压力的行为反应非常重要的调节肽。生长抑素通过与 G 蛋白偶联的生长抑素受体结合发挥作用，其中第四种亚型（SSTR4）是一种特别重要的受体，介导镇痛、抗炎和抗抑郁作用而没有内分泌作用。因此，SSTR4 激动剂是很有前途的候选药物。虽然了解 SST 的原子分辨率结合模式对于药物开发至关重要，但 SSTR4 及其复合物的结构实验阐明仍在等待中。在本研究中，使用无偏、盲目的对接方法生成了生长抑素-SSTR4 复合物的结构。除了静态结构外，还通过显式水分子动力学（MD）计算阐明了 SST 的结合机制，并区分了关键的结合模式（外部、中间和内部）。确定了受体和 SST 两侧的重要残基。SST 与 SSTR4 和 2 的结合能比较提供了受体亚型选择性的残基水平解释。计算得到的结构与现有实验结果吻合较好，表明生长抑素的结合是通过必需的结合模式和诱导契合机制来实现的。所确定的结合模式和相应的关键残基为靶向 SSTR4 的未来药物设计提供了有用的信息。
