Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins
Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins
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DOI：
10.1073/pnas.0307953101
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发表时间：
2004-04-06
影响因子：
11.1
通讯作者：
Sodroski, JG
中科院分区：
文献类型：
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作者：
Si, ZH;Madani, N;Sodroski, JG
当与CD4受体相互作用时，HIV gp120包膜糖蛋白发生构象变化，允许与趋化因子受体结合。受体结合被认为会导致gp41跨膜包膜糖蛋白的构象变化，包括产生和/或暴露由三个七肽重复序列（HR）组成的卷曲线圈。gp41的HR2区域随后与这个卷曲的线圈相互作用，导致六螺旋束的组装，促进病毒和靶细胞膜的融合。在这里，我们发现CD4结合到gp120诱导gp41 HR1卷曲线圈的形成和/或暴露在一个不涉及gp120脱落的过程中，这取决于gp160包膜糖蛋白前体的蛋白水解成熟。重要的是，BMS-806和相关的HIV-1进入抑制剂结合gp120并阻断Hill暴露的CD4诱导，而不显著影响CD4结合。此外，这些化合物不会破坏gp120-趋化因子受体结合或gp41中HR1-HR2的相互作用。因此，这些研究确定了gp120-gp41的受体诱导构象重排，这对于cd4依赖性和cd4非依赖性HIV-1的进入都很重要，并且容易受到低分子量化合物的抑制。
When interacting with the CD4 receptor, the HIV gp120 envelope glycoprotein undergoes conformational changes that allow binding to the chemokine receptor. Receptor binding is proposed to lead to conformational changes in the gp41 transmembrane envelope glycoprotein involving the creation and/or exposure of a coiled coil consisting of three heptad repeat (HR) sequences. The subsequent interaction of the HR2 region of gp41 with this coiled coil results in the assembly of a six-helix bundle that promotes the fusion of the viral and target cell membranes. Here we show that CD4 binding to gp120 induces the formation and/or exposure of the gp41 HR1 coiled coil in a process that does not involve gp120 shedding and that depends on the proteolytic maturation of the gp160 envelope glycoprotein precursor. Importantly, BMS-806 and related HIV-1 entry inhibitors bind gp120 and block the CD4 induction of Hill exposure without significantly affecting CD4 binding. Moreover, these compounds do not disrupt gp120-chemokine receptor binding or the HR1-HR2 interaction within gp41. These studies thus define a receptor-induced conformational rearrangement of gp120-gp41 that is important for both CD4-dependent and CD4-independent HIV-1 entry and is susceptible to inhibition by low-molecular-weight compounds.