PDF(Pubmed)
Abstract：
HIV infection remains a global health issue plagued by drug resistance and virological failure. Natural polymorphisms (NPs) contained within several African and Brazilian protease (PR) variants have been shown to induce a conformational landscape of more closed conformations compared to the sequence of subtype B prevalent in North America and Western Europe. Here we demonstrate through experimental pulsed EPR distance measurements and molecular dynamic (MD) simulations that the two common NPs D60E and I62V found within subtypes F and H can induce a closed conformation when introduced into HIV-1PR subtype B. Specifically, D60E alters the conformation in subtype B through the formation of a salt bridge with residue K43 contained within the nexus between the flap and hinge region of the HIV-1 PR fold. On the other hand, I62V modulates the packing of the hydrophobic cluster of the cantilever and fulcrum, also resulting in a more closed conformation.
摘要：
艾滋病毒感染仍然是一个全球性的健康问题，受到耐药性和病毒学失败的困扰。与北美和西欧流行的B亚型序列相比，几种非洲和巴西蛋白酶（PR）变体中包含的自然多态性（NP）已显示出诱导更封闭构象的构象景观。在这里，我们通过实验脉冲EPR距离测量和分子动力学（MD）模拟证明，在F和H亚型中发现的两种常见NPsD60E和I62V在引入HIV-1PR亚型B时可以诱导闭合构象。D60E通过形成盐桥来改变亚型B的构象,其中残基K43包含在HIV-1PR折叠的瓣和铰链区之间的连结内。另一方面,I62V调制悬臂和支点的疏水簇的堆积，也导致更封闭的构象。
