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色氨酰环（Trp-Cage）对 GLP-1R 激动剂 Exenatide 衍生物的功能和稳定性的影响。

Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives.

机构信息

HUN-REN-ELTE Protein Modeling Research Group, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary.

Laboratory of Structural Chemistry and Biology, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary.

出版信息

J Med Chem. 2024 Sep 26;67(18):16757-16772. doi: 10.1021/acs.jmedchem.4c01553. Epub 2024 Sep 10.

DOI:10.1021/acs.jmedchem.4c01553
PMID:39254428
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11440607/
Abstract

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.

摘要

Exenatide（Ex4），一种 GLP-1 肠促胰岛素类似多肽，是一种有效的糖尿病和肥胖症治疗药物。我们强调了 Ex4 的结构稳定色氨酸笼（Tc）基序在调节 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呈反比关系。分子动力学模拟结合刚体分段协议来分析动态连通性表明，受约束的 Tc 基序在受体-配体复合物内保持完整，但干扰 GLP-1R 细胞外侧的主要稳定接触和识别位点之一，使激素模拟物的 N 端激活区域移位，并限制 GLP-1R 的主要信号转导装置 TM6 的自由运动。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/bc9f0baacc7f/jm4c01553_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/e99ba496e513/jm4c01553_0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/9809af42a258/jm4c01553_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/43694498eaa7/jm4c01553_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/bc9f0baacc7f/jm4c01553_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/e99ba496e513/jm4c01553_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/0b58dfc7250f/jm4c01553_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/c064d6e1da29/jm4c01553_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/e33b3ab32053/jm4c01553_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/9809af42a258/jm4c01553_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/43694498eaa7/jm4c01553_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c92/11440607/bc9f0baacc7f/jm4c01553_0007.jpg

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