Structure and Function of Somatostatin and its Receptors in Endocrinology.

IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Endocrine reviews Pub Date : 2024-08-08 DOI:10.1210/endrev/bnae022
Bo Zhang, Li Xue, Zhe Bao Wu
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Abstract

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.

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内分泌学中的促生长素及其受体的结构和功能。
奥曲肽 (OCT)、兰雷奥肽和帕司雷奥肽等体生长抑素类似物作为体生长抑素受体配体 (SRL) 起作用,是治疗肢端肥大症的主要药物。这些配体也是神经内分泌肿瘤(NET)放射治疗和成像的重要分子。体生长抑素受体(SSTRs)是典型的 G 蛋白偶联蛋白(GPCRs),在新陈代谢、生长以及激素紊乱、神经系统疾病和癌症等病理情况中发挥作用。低温电子显微镜(cryo-EM)结合蛋白质结构预测平台 AlphaFold 已被用于确定许多蛋白质的三维结构。最近,几个研究小组发表了一系列论文,展示了 SSTR2 的三维结构,包括与不同配体结合的非活性/活性 SSTR2-G 蛋白复合物的三维结构。研究结果揭示了有助于配体结合袋的残基,并证明体生长抑素类似物中的 Trp8-Lys9(W-K 基团)是稳定结合袋底部的关键基团。在这篇综述中,我们将讨论有关 SSTR 和 SRL 结构分析的最新发现、结构数据与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。
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来源期刊
Endocrine reviews
Endocrine reviews 医学-内分泌学与代谢
CiteScore
42.00
自引率
1.00%
发文量
29
期刊介绍: Endocrine Reviews, published bimonthly, features concise timely reviews updating key mechanistic and clinical concepts, alongside comprehensive, authoritative articles covering both experimental and clinical endocrinology themes. The journal considers topics informing clinical practice based on emerging and established evidence from clinical research. It also reviews advances in endocrine science stemming from studies in cell biology, immunology, pharmacology, genetics, molecular biology, neuroscience, reproductive medicine, and pediatric endocrinology.
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