Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor

Abstract

Ebola virus (EBOV) entry requires the surface glycoprotein (GP) to initiate attachment and fusion of viral and host membranes. Here we report the crystal structure of EBOV GP in its trimeric, pre-fusion conformation (GP1+GP2) bound to a neutralizing antibody, KZ52, derived from a human survivor of the 1995 Kikwit outbreak. Three GP1 viral attachment subunits assemble to form a chalice, cradled by the GP2 fusion subunits, while a novel glycan cap and projected mucin-like domain restrict access to the conserved receptor-binding site sequestered in the chalice bowl. The glycocalyx surrounding GP is likely central to immune evasion and may explain why survivors have insignificant neutralizing antibody titres. KZ52 recognizes a protein epitope at the chalice base where it clamps several regions of the pre-fusion GP2 to the amino terminus of GP1. This structure provides a template for unravelling the mechanism of EBOV GP-mediated fusion and for future immunotherapeutic development. The Ebola virus, one of the most feared of pathogens, causes a severe haemorrhagic fever with up to 90% human mortality. Since 1994, outbreaks of the virus have increased fourfold. Although initial vaccine trials in primates have shown promise, no vaccines or post-exposure treatments are yet available. And it is still not clear why the virus is so pathogenic or why the immune response is so weak in fatal cases. A team from The Scripps Research Institute has now determined the crystal structure of the trimeric Ebola virus glycoprotein bound to a neutralizing antibody isolated from a human survivor. The structure reveals a putative receptor-binding site sequestered in a bowl of a chalice formed by three GP1 viral attachment subunits (in shades blue in the molecular surface model on the cover), cradled by three GP2 fusion subunits (coloured white). Access to the site is restricted by a glycan cap and a protruding mucin-like domain. The antibody (in yellow) bridges the GP1 and GP2 subunits and is specific for the prefusion, viral surface conformation of GP2. Cover graphics by Christina Corbaci & Michael Pique. The crystal structure of Ebola virus glycoprotein is shown in complex with a neutralizing antibody. The structure suggests that the antibody prevents infection by preventing conformational changes of GP2 required for fusion.