Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives,Journal of Medicinal Chemistry

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Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-10 , DOI: 10.1021/acs.jmedchem.4c01553
Dániel Horváth _{1,

2} , Pál Stráner _{1,

2} , Nóra Taricska _{1,

2} , Zsolt Fazekas _{2,

3} , Dóra K Menyhárd _{1,

2,

4} , András Perczel _{1,

2,

4}

Affiliation

Exenatide (Ex4), a GLP-1 incretin mimetic polypeptide, is an effective therapeutic agent against diabetes and obesity. We highlight the indirect role of Ex4’s structure-stabilizing Trp-cage (Tc) motif in governing GLP-1 receptor (GLP-1R) signal transduction. We use various Ex4 derivatives to explore how Tc compactness influences thermal stability, aggregation, enhancement of insulin secretion, and GLP-1R binding. We found that Ex4 variants decorated with fortified Tc motifs exhibit increased resistance to unfolding and aggregation but show an inverse relationship between the bioactivity and stability. Molecular dynamics simulations coupled with a rigid-body segmentation protocol to analyze dynamic interconnectedness revealed that the constrained Tc motifs remain intact within the receptor–ligand complexes but interfere with one of the major stabilizing contacts and recognition loci on the extracellular side of GLP-1R, dislodging the N-terminal activating region of the hormone mimetics, and restrict the free movement of TM6, the main signal transduction device of GLP-1R.

中文翻译：

Trp-Cage 对 GLP-1R 激动剂艾塞那肽衍生物功能和稳定性的影响

艾塞那肽（Ex4）是一种 GLP-1 肠促胰岛素模拟多肽，是一种对抗糖尿病和肥胖症的有效治疗剂。我们强调了 Ex4 的结构稳定 Trp-cage （Tc）基序在控制 GLP-1 受体（GLP-1R）信号转导中的间接作用。我们使用各种 Ex4 衍生物来探索 Tc 紧凑性如何影响热稳定性、聚集、胰岛素分泌增强和 GLP-1R 结合。我们发现，用强化 Tc 基序修饰的 Ex4 变体表现出对展开和聚集的抵抗力增加，但生物活性和稳定性之间存在负关系。分子动力学模拟与刚体分割方案相结合以分析动态互连性，表明受约束的 Tc 基序在受体-配体复合物内保持完整，但干扰了 GLP-1R 细胞外侧的主要稳定触点和识别位点之一，移动了激素模拟物的 N 末端激活区域，并限制了 TM6 的自由运动， GLP-1R 的主要信号转导装置。

更新日期：2024-09-10

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