Somatostatin analogs, such as octreotide (OCT), lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors (NETs). Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins (GPCRs) that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy (cryo-EM) combined with the protein structure prediction platform AlphaFold has been used to determine the three-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the three-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

中文翻译：

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生长抑素及其受体在内分泌学中的结构和功能。


生长抑素类似物，如奥曲肽（OCT）、兰瑞肽和帕瑞肽，作为生长抑素受体配体（SRL），是用于治疗肢端肥大症的主要药物。这些配体也用作神经内分泌肿瘤（NET）放射治疗和成像的重要分子。生长抑素受体 (SSTR) 是典型的 G 蛋白偶联蛋白 (GPCR)，在新陈代谢、生长和激素紊乱、神经系统疾病和癌症等病理状况中发挥作用。低温电子显微镜（cryo-EM）结合蛋白质结构预测平台AlphaFold已被用来确定许多蛋白质的三维结构。最近，几个小组发表了一系列论文，阐述了 SSTR2 的三维结构，包括与不同配体结合的失活/激活的 SSTR2-G 蛋白复合物的结构。结果揭示了有助于配体结合袋的残基，并证明生长抑素类似物中的Trp8-Lys9（WK基序）是稳定结合袋底部的关键基序。在这篇综述中，我们讨论了与 SSTR 和 SRL 结构分析相关的最新发现、结构数据和临床发现之间的关系以及基于结构的新型疗法的未来发展。