Biophysical Characterization of p51 and p66 Monomers of HIV-1 Reverse Transcriptase with Their Inhibitors

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY The Protein Journal Pub Date : 2023-09-20 DOI:10.1007/s10930-023-10156-y
Supaphorn Seetaha, Nuntaporn Kamonsutthipaijit, Maho Yagi-Utsumi, Yanaka Seako, Takumi Yamaguchi, Supa Hannongbua, Koichi Kato, Kiattawee Choowongkomon
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Abstract

Human immunodeficiency virus (HIV)-1 reverse transcriptase (HIV-1 RT) is responsible for the transcription of viral RNA genomes into DNA genomes and has become an important target for the treatment of acquired immune deficiency syndrome (AIDS). This study used biophysical techniques to characterize the HIV-1 RT structure, monomer forms, and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) bound forms. Inactive p66W401A and p51W401A were selected as models to study the HIV-1 RT monomer structures. Nuclear magnetic resonance (NMR) spectroscopy revealed that the unliganded forms of p66W401A protein and p51W401A protein had similar conformation to each other in solution. The complexes of p66W401A or p51W401A with inhibitors showed similar conformations to p66 in the RT heterodimer bound to the NNRTIs. Furthermore, the results of paramagnetic relaxation enhancement (PRE)-assisted NMR revealed that the unliganded forms of the p66W401A and p51W401A conformations were different from the unliganded heterodimer, characterized by a greater distance between the fingers and thumb subdomains. Small-angle X-ray scattering (SAXS) experiments confirmed that p66W401A and p51W401A can bind with inhibitors, similar to the p66/p51 heterodimer. The findings of this study increase the structural knowledge base of HIV-1 RT monomers, which may be helpful in the future design of potent viral inhibitors.

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HIV-1逆转录酶p51和p66单体及其抑制剂的生物物理特性。
人类免疫缺陷病毒(HIV)-1逆转录酶(HIV-1RT)负责将病毒RNA基因组转录为DNA基因组,已成为治疗获得性免疫缺陷综合征(AIDS)的重要靶点。本研究使用生物物理技术来表征HIV-1 RT的结构、单体形式和非核苷逆转录酶抑制剂(NNRTI)结合形式。选择无活性的p66W401A和p51W401A作为模型来研究HIV-1RT单体结构。核磁共振(NMR)谱显示,p66W401A蛋白和p51W401A蛋白在溶液中具有相似的构象。p66W401A或p51W401A与抑制剂的复合物在与NNRTI结合的RT异二聚体中显示出与p66相似的构象。此外,顺磁弛豫增强(PRE)辅助NMR的结果表明,p66W401A和p51W401A构象的未标记形式与未标记的异二聚体不同,其特征在于手指和拇指亚结构域之间的距离更大。小角度X射线散射(SAXS)实验证实,p66W401A和p51W401A可以与抑制剂结合,类似于p66/p51异二聚体。这项研究的发现增加了HIV-1 RT单体的结构知识库,这可能有助于未来设计有效的病毒抑制剂。
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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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