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首页> 外文期刊>Journal of Molecular Biology >Structural and Thermodynamic Analysis of HIV-1 Fusion Inhibition Using Small gp41 Mimetic Proteins
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Structural and Thermodynamic Analysis of HIV-1 Fusion Inhibition Using Small gp41 Mimetic Proteins

机译：使用小GP41模拟蛋白的HIV-1融合抑制的结构和热力学分析

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Development of effective inhibitors of the fusion between HIV-1 and the host cell membrane mediated by gp41 continues to be a grand challenge due to an incomplete understanding of the molecular and mechanistic details of the fusion process. We previously developed single-chain, chimeric proteins (named covNHR) that accurately mimic the N-heptad repeat (NHR) region of gp41 in a highly stable coiled-coil conformation. These molecules bind strongly to peptides derived from the gp41 C-heptad repeat (CHR) and are potent and broad HIV-1 inhibitors. Here, we investigated two covNHR variants differing in two mutations, V10E and Q123R (equivalent to V38E and Q40R in gp41 sequence) that reproduce the effect of HIV-1 mutations associated with resistance to fusion inhibitors, such as T20 (enfuvirtide). A detailed calorimetric analysis of the binding between the covNHR proteins and CHR peptides (C34 and T20) reveals drastic changes in affinity due to the mutations as a result of local changes in interactions at the site of T20 resistance. The crystallographic structure of the covNHR:C34 complex shows a virtually identical CHR NHR binding interface to that of the post-fusion structure of gp41 and underlines an important role of buried interfacial water molecules in binding affinity and in development of resistance against CHR peptides. Despite the great difference in affinity, both covNHR variants demonstrate strong inhibitory activity for a wide variety of HIV-1 strains. These properties support the high potential of these covNHR proteins as new potent HIV-1 inhibitors. Our results may guide future inhibition approaches. (C) 2019 Elsevier Ltd. All rights reserved.
机译：由于对融合过程的分子和机械细节不完全了解，HIV-1与GP41介导的宿主细胞膜之间的融合的有效抑制剂的研制仍然是一个大挑战。我们以前开发了单链，嵌合蛋白（命名为CoVNHR），可准确地模仿GP41的N-庚段重复（NHR）区域，在高度稳定的卷绕线圈构象中。这些分子强烈地粘合到衍生自GP41 C-庚段重复（CHR）的肽，并且是有效的和宽的HIV-1抑制剂。在此，我们研究了两个突变，V10E和Q123R（相当于GP41序列中的Q123R（相当于V38E和Q40R）的两种CoVNR变体，其再现与抗融合剂抗性相关的HIV-1突变的影响，例如T20（ENFVirtiDe）。 CoVNHR蛋白和Chr肽之间的结合的详细量热分析（C34和T20）显示由于T20抗性位点的局部相互作用的局部变化导致突变引起的亲和力的剧烈变化。 CoVNHR：C34复合物的晶体结构显示了GP41的融合结构的几乎相同的CHR NHR结合界面，并强调了掩埋界面水分子在结合亲和力和抗性对CHR肽的抗性发展中的重要作用。尽管亲和力有很大差异，CoVNHR变体都表现出各种HIV-1菌株的强抑制活性。这些性质支持这些CoVNHR蛋白的高潜力作为新的强效HIV-1抑制剂。我们的结果可能引导未来的抑制方法。 （c）2019 Elsevier Ltd.保留所有权利。

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