lanreotide和pasireotide与生长抑素受体1结合模式的结构见解

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI:10.1016/j.apsb.2025.03.043

Zicheng Zeng , Qiwen Liao , Shiyi Gan , Xinyu Li , Tiantian Xiong , Lezhi Xu , Dan Li , Yunlu Jiang , Jing Chen , Richard Ye , Yang Du , Thiansze Wong

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引用次数: 0

摘要

生长抑素受体1 （SSTR1）是多种神经内分泌和肿瘤疾病的重要治疗靶点。目前针对sstr1的治疗，包括第一代生长抑素类似物lanreotide （Lan）和第二代类似物pasireotide (Pas)，显示出希望，但遇到了与选择性和有效性相关的挑战。本研究展示了SSTR1与Lan或Pas络合的高分辨率低温电镜结构，揭示了其独特的配体结合和激活机制。这些结构说明了每种配体诱导的SSTR1正构口袋中独特的构象变化，这对受体激活和配体选择性至关重要。结合生化分析和分子动力学模拟，我们的研究结果提供了SSTR家族内结合特性的比较分析，突出了Lan和Pas在SSTR1激活方面的细微差异。这些见解为设计下一代疗法铺平了道路，通过改进受体亚型选择性，提高疗效，减少副作用。

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Structural insights into the binding modes of lanreotide and pasireotide with somatostatin receptor 1

Somatostatin receptor 1 (SSTR1) is a crucial therapeutic target for various neuroendocrine and oncological disorders. Current SSTR1-targeted treatments, including the first-generation somatostatin analog lanreotide (Lan) and the second-generation analog pasireotide (Pas), show promise but encounter challenges related to selectivity and efficacy. This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas, revealing the distinct mechanisms of ligand-binding and activation. These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand, which are critical for receptor activation and ligand selectivity. Combined with the biochemical assays and molecular dynamics simulations, our results provide a comparative analysis of binding characteristics within the SSTR family, highlighting subtle differences in SSTR1 activation by Lan and Pas. These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.

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来源期刊

Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics

CiteScore

22.40

自引率

5.50%

发文量

1051

审稿时长

19 weeks

期刊介绍： The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.