通过实验和计算方法揭示细菌HslV蛋白酶与三嗪衍生物的激活电位。

IF 1.4 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sana Aurangzeb, Muhammad Aurongzeb, Mehwish Hamid, Yasmeen Rashid, Shahbaz Shamim, Khalid Mohammed Khan, Tariq Aziz, Nawal Al-Hoshani, Maher S. Alwethaynani, Fakhria A. Al-Joufi
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引用次数: 0

摘要

细菌HslVU酶复合体由两部分组成:HslV蛋白酶和HslU atp酶。这个复合体在结构和序列上都与真核生物蛋白酶体相似。HslV在与HslU结合后变得功能活跃,HslU将其c端螺旋插入HslV二聚体内的保守凹槽中。这种相互作用触发变构调节,从而启动HslV的蛋白水解活性。由于HslVU系统存在于致病菌中,但在人类中不存在,因此它代表了抗菌药物开发的一个有希望的目标。本研究的重点是发现高激活HslV的小分子,导致有害细菌菌株过度的蛋白质降解。通过将计算模型与实验室分析相结合,确定了四种基于三嗪的化合物是HslV的有效激活剂。这些分子在对接模拟中表现出高的结合亲和力,良好的相互作用谱,以及在生化分析中的显著激活。它们的ED₅0值从0.37 μM到0.55 μM不等,表明效力强。此外,ADMET评估显示了理想的药代动力学和药物相似特性。总的来说,这项工作提出了有效的,非肽性的HslV蛋白酶的小分子激活剂,并为HslVU系统的化学调节提供了新的见解,为抗菌药物的发现提供了一条有希望的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Revealing the Bacterial HslV Protease Activation Potential with Triazine Derivatives via Experimental and Computational Approaches

The bacterial HslVU enzyme complex consists of two components: the HslV protease and the HslU ATPase. This complex share both structural and sequence similarities with the eukaryotic proteasome. HslV becomes functionally active upon engagement with HslU, which inserts its C-terminal helix into a conserved groove within the HslV dimer. This interaction triggers allosteric modulation, thereby initiating HslV’s proteolytic activity. Because the HslVU system is present in pathogenic bacteria but absent in humans, it represents a promising target for antibacterial drug development. This study focuses on the discovery of small molecules that hyperactivate HslV, leading to excessive protein degradation in harmful bacterial strains. By integrating computational modeling with laboratory assays, four triazine-based compounds were identified as potent activators of HslV. These molecules demonstrated high binding affinity in docking simulations, favorable interaction profiles, and significant activation in biochemical assays. Their ED₅₀ values ranged from 0.37 μM to 0.55 μM, indicating strong potency. Furthermore, ADMET evaluations revealed desirable pharmacokinetic and drug-likeness properties. Overall, this work presents effective, non-peptidic small-molecule activators of the HslV protease and provides new insights into chemical modulation of the HslVU system, offering a promising avenue for antibacterial drug discovery.

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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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