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
{"title":"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。","authors":"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","doi":"10.1007/s10930-025-10286-5","DOIUrl":null,"url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"44 5","pages":"639 - 653"},"PeriodicalIF":1.4000,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Revealing the Bacterial HslV Protease Activation Potential with Triazine Derivatives via Experimental and Computational Approaches\",\"authors\":\"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\",\"doi\":\"10.1007/s10930-025-10286-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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.</p></div>\",\"PeriodicalId\":793,\"journal\":{\"name\":\"The Protein Journal\",\"volume\":\"44 5\",\"pages\":\"639 - 653\"},\"PeriodicalIF\":1.4000,\"publicationDate\":\"2025-08-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Protein Journal\",\"FirstCategoryId\":\"2\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10930-025-10286-5\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Protein Journal","FirstCategoryId":"2","ListUrlMain":"https://link.springer.com/article/10.1007/s10930-025-10286-5","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
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.