Computational characterization of structural role of the non-active site mutation M36I of human immunodeficiency virus type 1 protease
Computational characterization of structural role of the non-active site mutation M36I of human immunodeficiency virus type 1 protease
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DOI：
10.1016/j.jmb.2007.04.081
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发表时间：
2007-07-13
影响因子：
5.6
通讯作者：
Hoshino, Tyuji
中科院分区：
文献类型：
--
作者：
Ode, Hirotaka;Matsuyama, Shou;Hoshino, Tyuji
人类免疫缺陷病毒1型（HIV-1）的一个突出特点是其高度的遗传变异性，这产生了病毒的多样性，并经常导致出现耐药突变体的严重问题。B亚型HIV-1在发达国家占主导地位，过去十年中，B亚型HIV-1造成的死亡率有所下降。相比之下，发展中国家的非B亚型病毒患者数量仍在增加。非亚型B病毒流行的原因之一是缺乏关于亚型B和非亚型B病毒之间的生物学和治疗差异的信息。M361是非B亚型HIV-1蛋白酶中最常见的多态性。然而，由于第36位残基位于蛋白酶的非活性位点，并且与任何配体没有直接相互作用，因此M361的结构作用仍然不清楚。在这里，我们进行了分子动力学（MD）模拟M361蛋白酶与奈非那韦复合物，并揭示了M361突变的影响。结果表明，M361调节蛋白酶的结合腔的大小。从我们的计算分析中也阐明了在非亚型B HIV-1蛋白酶中罕见出现D30 N变体的原因。(c)2007爱思唯尔有限公司保留所有权利。
A prominent characteristic of human immunodeficiency virus type 1 (HIV-1) is its high genetic variability, which generates diversity of the virus and often causes a serious problem of the emergence of drug-resistant mutants. Subtype B HIV-1 is dominant in advanced countries, and the mortality rate due to subtype B HIV-1 has been decreased during the past decade. In contrast, the number of patients with non-subtype B viruses is still increasing in developing countries. One of the reasons for the prevalence of non-subtype B viruses is lack of information about the biological and therapeutic differences between subtype B and non-subtype B viruses. M361 is the most frequently observed polymorphism in non-subtype B HIV-1 proteases. However, since the 36th residue is located at a non-active site of the protease and has no direct interaction with any ligands, the structural role of M361 remains unclear. Here, we performed molecular dynamics (MD) simulations of M361 protease in complex with nelfinavir and revealed the influence of the M361 mutation. The results show that M361 regulates the size of the binding cavity of the protease. The reason for the rare emergence of D30N variants in non-subtype B HIV-1 proteases was also clarified from our computational analysis. (c) 2007 Elsevier Ltd. All rights reserved.