Structural insights into the mechanisms of drug resistance in HIV-1 protease NL4-3
Structural insights into the mechanisms of drug resistance in HIV-1 protease NL4-3
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DOI：
10.1016/j.jmb.2005.11.094
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发表时间：
2006-03-03
影响因子：
5.6
通讯作者：
Stout, CD
中科院分区：
文献类型：
--
作者：
Heaslet, H;Kutilek, V;Stout, CD
对靶向HIV的抗逆转录病毒药物的耐药性的发展是治疗HIV-1感染个体中日益严重的临床问题。许多患者在使用抑制剂鸡尾酒（HAART疗法）治疗后产生耐药病毒株，其中包括多种蛋白酶抑制剂。因此，我们必须了解病毒蛋白，特别是HIV-1蛋白酶产生抗性的机制。我们已经确定了HIV-1蛋白酶NL 4 -3与有效的蛋白酶抑制剂TL-3在2.0埃分辨率的复合物的三维结构。我们还获得了与TL-3复合的含有一个（V82 A）、三个（V82 A、M461、F53 L）和六个（V82 A、M461、F53 L、V771、L241、L 63 P）点突变的NL 4 -3蛋白酶的三种突变形式的晶体结构。这三种蛋白酶突变体在TL-3存在下在离体选择压力下依次产生，并分别对TL-3表现出4倍、11倍和30倍的抗性。这一系列的蛋白酶晶体结构提供了深入了解的生化和结构机制，通过该酶可以克服抑制TL-3，同时恢复一些其天然的催化活性。(c)2005爱思唯尔有限公司保留所有权利。
The development of resistance to anti-retroviral drugs targeted against HIV is an increasing clinical problem in the treatment of HIV-1-infected individuals. Many patients develop drug-resistant strains of the virus after treatment with inhibitor cocktails (HAART therapy), which include multiple protease inhibitors. Therefore, it is imperative that we understand the mechanisms by which the viral proteins, in particular HlV-1 protease, develop resistance. We have determined the three-dimensional structure of HIV-1 protease NL4-3 in complex with the potent protease inhibitor TL-3 at 2.0 angstrom resolution. We have also obtained the crystal structures of three mutant forms of NL4-3 protease containing one (V82A), three (V82A, M461, F53L) and six (V82A, M461, F53L, V771, L241, L63P) point mutations in complex with TL-3. The three protease mutants arose sequentially under ex vivo selective pressure in the presence of TL-3, and exhibit fourfold, 11-fold, and 30-fold resistance to TL-3, respectively. This series of protease crystal structures offers insights into the biochemical and structural mechanisms by which the enzyme can overcome inhibition by TL-3 while recovering some of its native catalytic activity. (c) 2005 Elsevier Ltd. All rights reserved.