The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

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Guardado-Calvo, P. (P.), Atkovska, K. (K.), Jeffers, S.A. (S. A.), Grau, N. (N.), Backovic, M. (M.), Pérez-Vargas, J. (J.), … Rey, F.A. (F. A.). (2017). A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion. Science, 358(6363), 663–667. doi:10.1126/science.aal2712