Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS), Grenoble, France.
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
Elife. 2021 Apr 19;10:e65005. doi: 10.7554/eLife.65005.
The HIV-1 gp120/gp41 trimer undergoes a series of conformational changes in order to catalyze gp41-induced fusion of viral and cellular membranes. Here, we present the crystal structure of gp41 locked in a fusion intermediate state by an MPER-specific neutralizing antibody. The structure illustrates the conformational plasticity of the six membrane anchors arranged asymmetrically with the fusion peptides and the transmembrane regions pointing into different directions. Hinge regions located adjacent to the fusion peptide and the transmembrane region facilitate the conformational flexibility that allows high-affinity binding of broadly neutralizing anti-MPER antibodies. Molecular dynamics simulation of the MPER Ab-stabilized gp41 conformation reveals a possible transition pathway into the final post-fusion conformation with the central fusion peptides forming a hydrophobic core with flanking transmembrane regions. This suggests that MPER-specific broadly neutralizing antibodies can block final steps of refolding of the fusion peptide and the transmembrane region, which is required for completing membrane fusion.
HIV-1 gp120/gp41 三聚体发生一系列构象变化，以催化 gp41 诱导的病毒和细胞膜融合。在这里，我们展示了 gp41 被一种 MPER 特异性中和抗体锁定在融合中间状态的晶体结构。该结构说明了六个膜锚定的构象可塑性，它们不对称地排列融合肽和跨膜区域指向不同的方向。位于融合肽和跨膜区域附近的铰链区域促进了构象灵活性，从而允许高亲和力结合广谱中和抗 MPER 抗体。对 MPER Ab 稳定的 gp41 构象的分子动力学模拟揭示了一种可能的过渡途径，进入最终的融合后构象，其中中央融合肽形成一个疏水区，侧翼的跨膜区域。这表明，MPER 特异性广谱中和抗体可以阻止融合肽和跨膜区域的最终折叠，这是完成膜融合所必需的。
