The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20–21 hairpin. In both structures, the β20–21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.

中文翻译：

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具有进入抑制剂BMS-378806和BMS-626529的三聚体HIV包膜的晶体结构

HIV-1包膜（Env）尖峰是一种构象机器，可在融合前（封闭，CD4和CCR5结合）和融合后状态之间转换，以促进HIV-1进入细胞。尽管融合前的封闭构象是潜在的抑制靶标，但由于难以获得结构信息而阻碍了小分子前导的发展。在这里，我们用BMS-378806和衍生物BMS-626529报告了HIV-1-Env三聚体在3.8-Å分辨率下的晶体结构，其前药版本目前处于III期临床试验中。两位主要候选人都认识到一个诱导结合袋，该结合袋大部分不包含在溶剂中，并且包含来自保守螺旋和β20-21发夹的Env元素。在这两种结构中，β20-21区域均假定其构象不同于融合前封闭和CD4结合态。