Conserved hydrogen bonds and water molecules in MDR HIV-1 protease substrate complexes.
Conserved hydrogen bonds and water molecules in MDR HIV-1 protease substrate complexes.
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DOI：
10.1016/j.bbrc.2012.12.045
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发表时间：
2013-01-18
影响因子：
3.1
通讯作者：
Kovari LC
中科院分区：
文献类型：
--
作者：
Liu Z;Wang Y;Yedidi RS;Dewdney TG;Reiter SJ;Brunzelle JS;Kovari IA;Kovari LC
高效抗逆转录病毒疗法（HAART）在抗艾滋病毒治疗中的成功受到迅速发展的耐药性的严重影响。HIV-1蛋白酶抑制剂，HAART的一部分，正在失去其抑制靶标的效力和功效。多重耐药（MDR） 769 HIV-1蛋白酶（在残基10、36、46、54、62、63、71、82、84、90处发生耐药突变）被选为本研究的研究对象，以了解其与天然底物的结合。分析了MDR769 HIV-1蛋白酶底物七肽复合物的9个晶体结构，揭示了其中的保守结构元素，为抗MDR HIV-1蛋白酶的药物设计提供依据。我们的结构研究表明，蛋白酶和底物肽之间高度保守的氢键，以及保守的晶体水分子，在底物识别、底物稳定和蛋白酶稳定中起着至关重要的作用。此外，缺少关键的皮瓣配体桥接水分子可能意味着MDR769 HIV-1蛋白酶的催化机制与野生型（WT） HIV-1蛋白酶不同。
The success of highly active antiretroviral therapy (HAART) in anti-HIV therapy is severely compromised by the rapidly developing drug resistance. HIV-1 protease inhibitors, part of HAART, are losing their potency and efficacy in inhibiting the target. Multi-drug resistant (MDR) 769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, 90) was selected for the present study to understand the binding to its natural substrates. The nine crystal structures of MDR769 HIV-1 protease substrate hepta-peptide complexes were analyzed in order to reveal the conserved structural elements for the purpose of drug design against MDR HIV-1 protease. Our structural studies demonstrated that highly conserved hydrogen bonds between the protease and substrate peptides, together with the conserved crystallographic water molecules, played a crucial role in the substrate recognition, substrate stabilization and protease stabilization. In addition, the absence of the key flap-ligand bridging water molecule might imply a different catalytic mechanism of MDR769 HIV-1 protease compared to that of wild type (WT) HIV-1 protease.