Post-Catalytic Complexes with Emtricitabine or Stavudine and HIV-1 Reverse Transcriptase Reveal New Mechanistic Insights for Nucleotide Incorporation and Drug Resistance.
Post-Catalytic Complexes with Emtricitabine or Stavudine and HIV-1 Reverse Transcriptase Reveal New Mechanistic Insights for Nucleotide Incorporation and Drug Resistance.
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催化后复合物与Emtritebine或Stavudine和HIV-1逆转录酶揭示了核苷酸掺入和耐药性的新机械见解。
DOI：
10.3390/molecules25204868
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发表时间：
2020-10-21
期刊：
影响因子：
--
通讯作者：
Anderson KS
中科院分区：
文献类型：
--
作者：
Bertoletti N;Chan AH;Schinazi RF;Anderson KS
人类免疫缺陷病毒1（HIV-1）感染是一个全球性的健康问题，因为既没有治愈方法，也没有疫苗。然而，高效抗逆转录病毒治疗（HAART）已提高了获得性免疫缺陷综合征（AIDS）患者的预期寿命。核苷类逆转录酶抑制剂（NRTI）几乎存在于所有的HAART和靶向逆转录酶（RT）中，RT是病毒的必需酶。尽管NRTI非常有效，但它们具有由RT抗性引起的局限性。RT对NRTIs耐药的主要机制是歧视和切除。了解识别和切除的分子机制对于开发更有效和选择性的NRTIs至关重要。使用蛋白质X-射线晶体学，我们确定了RT在其后催化状态下与恩曲他滨，（-）FTC或司他夫定（d4 T）复合的第一晶体结构。我们的结构研究提供了一个框架，了解RT如何区分NRTIs和天然核苷酸，并了解要求（-）FTC进行构象变化的成功纳入RT。RT的晶体结构的后催化复合物与d4 T提供了一个“快照”，考虑如何RT开发电阻d4 T通过切除的可能机制。本文报道的研究结果将有助于下一代NRTIs的开发。
Human immunodeficiency virus 1 (HIV-1) infection is a global health issue since neither a cure nor a vaccine is available. However, the highly active antiretroviral therapy (HAART) has improved the life expectancy for patients with acquired immunodeficiency syndrome (AIDS). Nucleoside reverse transcriptase inhibitors (NRTIs) are in almost all HAART and target reverse transcriptase (RT), an essential enzyme for the virus. Even though NRTIs are highly effective, they have limitations caused by RT resistance. The main mechanisms of RT resistance to NRTIs are discrimination and excision. Understanding the molecular mechanisms for discrimination and excision are essential to develop more potent and selective NRTIs. Using protein X-ray crystallography, we determined the first crystal structure of RT in its post-catalytic state in complex with emtricitabine, (-)FTC or stavudine (d4T). Our structural studies provide the framework for understanding how RT discriminates between NRTIs and natural nucleotides, and for understanding the requirement of (-)FTC to undergo a conformation change for successful incorporation by RT. The crystal structure of RT in post-catalytic complex with d4T provides a “snapshot” for considering the possible mechanism of how RT develops resistance for d4T via excision. The findings reported herein will contribute to the development of next generation NRTIs.
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影响因子：
4.1
作者：
Markowitz M;Sarafianos SG
通讯作者：
Sarafianos SG
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.9
作者：
Feng, JY;Murakami, E;Anderson, KS
通讯作者：
Anderson, KS
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
1
作者：
Holec AD;Mandal S;Prathipati PK;Destache CJ
通讯作者：
Destache CJ