辅助突变维持耐药性 HIV-1 蛋白酶的稳定性。
Accessory mutations maintain stability in drug-resistant HIV-1 protease.
机构信息
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
出版信息
J Mol Biol. 2011 Jul 22;410(4):756-60. doi: 10.1016/j.jmb.2011.03.038.
Abstract
The underlying mechanisms driving the evolution of drug resistance in human immunodeficiency virus (HIV) are only partially understood. We investigated the evolutionary cost of the major resistance mutations in HIV-1 protease in terms of protein stability. The accumulation of resistance mutations destabilizes the protease, limiting further adaptation. From an analysis of clinical isolates, we identified specific accessory mutations that were able to restore the stability of the protease or even increase it beyond the wild-type baseline. Resistance mutations were also found to decrease the activity of HIV protease near neutral pH values, while incorporating stabilizing mutations improved the enzyme's pH tolerance. These findings help us to explain the prevalence of mutations located far from the active site and underscore the importance of protein stability during the evolution of drug resistance in HIV.
摘要
人类免疫缺陷病毒（HIV）耐药性演变的潜在机制尚未完全阐明。我们研究了 HIV-1 蛋白酶主要耐药突变的蛋白质稳定性方面的进化代价。耐药突变的积累会使蛋白酶不稳定，限制进一步的适应性进化。通过对临床分离株的分析，我们发现了一些特定的辅助突变，这些突变能够恢复蛋白酶的稳定性，甚至使其稳定性超过野生型基线。耐药突变还会降低 HIV 蛋白酶在接近中性 pH 值时的活性，而加入稳定突变则会提高酶的 pH 值耐受性。这些发现有助于我们解释远离活性部位的突变普遍存在的原因，并强调了在 HIV 耐药性进化过程中蛋白质稳定性的重要性。
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