TY - JOUR TI - Structure of HIV-1 gp41 with its membrane anchors targeted by neutralizing antibodies AU - Caillat, Christophe AU - Guilligay, Delphine AU - Torralba, Johana AU - Friedrich, Nikolas AU - Nieva, Jose L AU - Trkola, Alexandra AU - Chipot, Christophe J AU - Dehez, François L AU - Weissenhorn, Winfried A2 - Brunger, Axel T A2 - Dötsch, Volker VL - 10 PY - 2021 DA - 2021/04/19 SP - e65005 C1 - eLife 2021;10:e65005 DO - 10.7554/eLife.65005 UR - https://doi.org/10.7554/eLife.65005 AB - 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. KW - HIV-1 KW - gp41 KW - membrane fusion KW - LN01 KW - 4E10 KW - 2H10 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -