HIV-1 逆转录酶与抑制剂β-崖柏醇在 RNase H 活性部位结合的结构。
Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site.
机构信息
Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA.
Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA.
出版信息
Structure. 2009 Dec 9;17(12):1625-1635. doi: 10.1016/j.str.2009.09.016.
Abstract
Novel inhibitors are needed to counteract the rapid emergence of drug-resistant HIV variants. HIV-1 reverse transcriptase (RT) has both DNA polymerase and RNase H (RNH) enzymatic activities, but approved drugs that inhibit RT target the polymerase. Inhibitors that act against new targets, such as RNH, should be effective against all of the current drug-resistant variants. Here, we present 2.80 A and 2.04 A resolution crystal structures of an RNH inhibitor, beta-thujaplicinol, bound at the RNH active site of both HIV-1 RT and an isolated RNH domain. beta-thujaplicinol chelates two divalent metal ions at the RNH active site. We provide biochemical evidence that beta-thujaplicinol is a slow-binding RNH inhibitor with noncompetitive kinetics and suggest that it forms a tropylium ion that interacts favorably with RT and the RNA:DNA substrate.
摘要
需要新型抑制剂来对抗 HIV 耐药变体的快速出现。HIV-1 逆转录酶 (RT) 具有 DNA 聚合酶和核糖核酸酶 H (RNH) 酶活性，但已批准的抑制 RT 的药物针对聚合酶。针对新靶点（如 RNH）的抑制剂应该对所有当前的耐药变体有效。在这里，我们展示了 HIV-1 RT 和分离的 RNH 结构域的 RNH 活性部位结合的 RNH 抑制剂 beta-thujaplicinol 的 2.80 A 和 2.04 A 分辨率晶体结构。beta-thujaplicinol 在 RNH 活性部位螯合两个二价金属离子。我们提供了生化证据表明 beta-thujaplicinol 是一种具有非竞争动力学的慢结合 RNH 抑制剂，并提出它形成一个与 RT 和 RNA:DNA 底物相互作用良好的三价氧离子。
相似文献
1
Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site.HIV-1 逆转录酶与抑制剂β-崖柏醇在 RNase H 活性部位结合的结构。
Structure. 2009 Dec 9;17(12):1625-1635. doi: 10.1016/j.str.2009.09.016.
2
Transient kinetic analyses of the ribonuclease H cleavage activity of HIV-1 reverse transcriptase in complex with efavirenz and/or a β-thujaplicinol analogue.HIV-1 逆转录酶与依非韦伦和/或β-雪松醇类似物复合物的核糖核酸酶 H 切割活性的瞬态动力学分析。
Biochem J. 2013 Oct 15;455(2):179-84. doi: 10.1042/BJ20130850.
3
Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones.羟基化托酚酮对HIV-1逆转录酶相关核糖核酸酶H活性的选择性抑制作用
Nucleic Acids Res. 2005 Mar 1;33(4):1249-56. doi: 10.1093/nar/gki268. Print 2005.
4
HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site.结合有核糖核酸酶H抑制剂二羟基苯甲酰萘基腙的HIV-1逆转录酶结构，该抑制剂结合于一个新位点。
ACS Chem Biol. 2006 Dec 20;1(11):702-12. doi: 10.1021/cb600303y.
5
A 2-Hydroxyisoquinoline-1,3-Dione Active-Site RNase H Inhibitor Binds in Multiple Modes to HIV-1 Reverse Transcriptase.一种 2-羟基异喹啉-1,3-二酮活性位点核糖核酸酶 H 抑制剂以多种模式结合到 HIV-1 逆转录酶上。
Antimicrob Agents Chemother. 2017 Sep 22;61(10). doi: 10.1128/AAC.01351-17. Print 2017 Oct.
6
Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNase H domain of HIV-1 reverse transcriptase and structure-activity analysis of inhibitor analogs.二羟基香豆素活性位点抑制剂与HIV-1逆转录酶的核糖核酸酶H结构域复合物的结构及抑制剂类似物的构效分析
J Mol Biol. 2014 Jul 15;426(14):2617-31. doi: 10.1016/j.jmb.2014.05.006. Epub 2014 May 17.
7
Developing and Evaluating Inhibitors against the RNase H Active Site of HIV-1 Reverse Transcriptase.开发并评估针对 HIV-1 逆转录酶 RNase H 活性部位的抑制剂。
J Virol. 2018 Jun 13;92(13). doi: 10.1128/JVI.02203-17. Print 2018 Jul 1.
8
Structural basis of the allosteric inhibitor interaction on the HIV-1 reverse transcriptase RNase H domain.HIV-1 逆转录酶 RNase H 结构域变构抑制剂相互作用的结构基础。
Chem Biol Drug Des. 2012 Nov;80(5):706-16. doi: 10.1111/cbdd.12010. Epub 2012 Aug 31.
9
Enzymatic Activities of RNase H Domains of HIV-1 Reverse Transcriptase with Substrate Binding Domains of Bacterial RNases H1 and H2.具有细菌核糖核酸酶H1和H2底物结合结构域的HIV-1逆转录酶核糖核酸酶H结构域的酶活性
Mol Biotechnol. 2015 Jun;57(6):526-38. doi: 10.1007/s12033-015-9846-5.
10
Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097.临床上相关的赖氨酸103天冬酰胺/酪氨酸181半胱氨酸双突变HIV-1逆转录酶与ATP和非核苷抑制剂HBY 097复合物的晶体结构。
J Mol Biol. 2007 Jan 5;365(1):77-89. doi: 10.1016/j.jmb.2006.08.097. Epub 2006 Sep 15.
引用本文的文献
1
The Evolution of Cell Culture Systems to Study Hepatitis B Virus Pathogenesis and Antiviral Susceptibility.用于研究乙型肝炎病毒发病机制和抗病毒敏感性的细胞培养系统的演变
Viruses. 2025 Jul 29;17(8):1057. doi: 10.3390/v17081057.
2
Discovery of Benzisothiazolone Derivatives as Bifunctional Inhibitors of HIV-1 Reverse Transcriptase DNA Polymerase and Ribonuclease H Activities.苯并异噻唑酮衍生物作为 HIV-1 逆转录酶 DNA 聚合酶和核糖核酸酶 H 双功能抑制剂的发现。
Biomolecules. 2024 Jul 9;14(7):819. doi: 10.3390/biom14070819.
3
Investigation of Kelussia Odoratissima and Angelica Sinensis Similarities in Zebrafish-based In-vivo Bioactivity Assays and Their Chemical Composition.基于斑马鱼的体内生物活性测定及其化学成分对香青兰和当归相似性的研究
Galen Med J. 2023 Jul 30;12:e2793. doi: 10.31661/gmj.v12i.2793. eCollection 2023.
4
Identification and assessment of the 1,6-dihydroxy-pyridin-2-one moiety as privileged scaffold for HBV ribonuclease H inhibition.鉴定和评估 1,6-二羟基吡啶-2-酮部分作为乙肝病毒核糖核酸酶 H 抑制的优势骨架。
Antiviral Res. 2024 Mar;223:105833. doi: 10.1016/j.antiviral.2024.105833. Epub 2024 Feb 5.
5
Antiviral Activity and Molecular Dynamics Simulation of Hops Compounds against Oropouche Virus ().啤酒花化合物对奥罗普切病毒的抗病毒活性及分子动力学模拟（）
Pharmaceutics. 2023 Dec 13;15(12):2769. doi: 10.3390/pharmaceutics15122769.
6
Data mining and molecular dynamics analysis to detect HIV-1 reverse transcriptase RNase H activity inhibitor.用于检测HIV-1逆转录酶核糖核酸酶H活性抑制剂的数据挖掘与分子动力学分析
Mol Divers. 2024 Aug;28(4):1869-1888. doi: 10.1007/s11030-023-10707-6. Epub 2023 Aug 10.
7
5-Nitro-3-(2-(4-phenylthiazol-2-yl)hydrazineylidene)indolin-2-one derivatives inhibit HIV-1 replication by a multitarget mechanism of action.5-硝基-3-(2-(4-苯基噻唑-2-基)腙基)吲哚啉-2-酮衍生物通过多靶点作用机制抑制 HIV-1 复制。
Front Cell Infect Microbiol. 2023 Jun 23;13:1193280. doi: 10.3389/fcimb.2023.1193280. eCollection 2023.
8
Predicted structure of the hepatitis B virus polymerase reveals an ancient conserved protein fold.乙型肝炎病毒聚合酶的预测结构揭示了一个古老的保守蛋白折叠。
Protein Sci. 2022 Oct;31(10):e4421. doi: 10.1002/pro.4421.
9
Metal coordinating inhibitors of Rift Valley fever virus replication.金属配位抑制剂抑制裂谷热病毒复制。
PLoS One. 2022 Sep 16;17(9):e0274266. doi: 10.1371/journal.pone.0274266. eCollection 2022.
10
Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies.从三十年的结构研究看 HIV-1 逆转录酶 (RT) 抑制和耐药性。
Viruses. 2022 May 11;14(5):1027. doi: 10.3390/v14051027.
本文引用的文献
1
Processing of X-ray diffraction data collected in oscillation mode.振荡模式下收集的X射线衍射数据的处理。
Methods Enzymol. 1997;276:307-26. doi: 10.1016/S0076-6879(97)76066-X.
2
HIV-1 reverse transcriptase can simultaneously engage its DNA/RNA substrate at both DNA polymerase and RNase H active sites: implications for RNase H inhibition.HIV-1逆转录酶可在DNA聚合酶和核糖核酸酶H活性位点同时结合其DNA/RNA底物：对核糖核酸酶H抑制的影响。
J Mol Biol. 2009 May 8;388(3):462-74. doi: 10.1016/j.jmb.2009.03.025. Epub 2009 Mar 13.
3
Crystal engineering of HIV-1 reverse transcriptase for structure-based drug design.用于基于结构的药物设计的HIV-1逆转录酶晶体工程
Nucleic Acids Res. 2008 Sep;36(15):5083-92. doi: 10.1093/nar/gkn464. Epub 2008 Aug 1.
4
The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral.萘啶酮GSK364735是一种新型、强效的1型人类免疫缺陷病毒整合酶抑制剂及抗逆转录病毒药物。
Antimicrob Agents Chemother. 2008 Mar;52(3):901-8. doi: 10.1128/AAC.01218-07. Epub 2007 Dec 26.
5
Structure of human RNase H1 complexed with an RNA/DNA hybrid: insight into HIV reverse transcription.与 RNA/DNA 杂交体复合的人核糖核酸酶 H1 的结构：对 HIV 逆转录的深入了解。
Mol Cell. 2007 Oct 26;28(2):264-76. doi: 10.1016/j.molcel.2007.08.015.
6
Substrate-dependent inhibition kinetics of an active site-directed inhibitor of ADAMTS-4 (Aggrecanase 1).ADAMTS-4（软骨聚集蛋白聚糖酶1）活性位点导向抑制剂的底物依赖性抑制动力学
Biochemistry. 2007 May 29;46(21):6393-401. doi: 10.1021/bi7000642. Epub 2007 May 8.
7
Economical parallel protein expression screening and scale-up in Escherichia coli.大肠杆菌中经济高效的平行蛋白质表达筛选与放大
J Struct Funct Genomics. 2006 Jun;7(2):101-8. doi: 10.1007/s10969-006-9013-0. Epub 2006 Dec 23.
8
HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site.结合有核糖核酸酶H抑制剂二羟基苯甲酰萘基腙的HIV-1逆转录酶结构，该抑制剂结合于一个新位点。
ACS Chem Biol. 2006 Dec 20;1(11):702-12. doi: 10.1021/cb600303y.
9
Recent progress in the design of small molecule inhibitors of HIV RNase H.HIV核糖核酸酶H小分子抑制剂设计的最新进展。
Curr Pharm Des. 2006;12(15):1909-22. doi: 10.2174/138161206776873653.
10
Mechanism of Mos1 transposition: insights from structural analysis.Mos1转座机制：结构分析带来的见解
EMBO J. 2006 Mar 22;25(6):1324-34. doi: 10.1038/sj.emboj.7601018. Epub 2006 Mar 2.
Zotero 插件