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Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion (1-7). GP is thus a primary target for the development of antiviral drugs. Here we report the first, to our knowledge, unliganded structure of EBOV GP, and high-resolution complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resolution apo structure gives a more complete and accurate picture of the molecule, and allows conformational changes introduced by antibody and receptor binding to be deciphered (8-10). Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equivalent tunnels from the other monomers of the trimer at the three-fold axis. Protein-drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14°C decrease in the protein melting temperature after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs., The recent outbreak of EBOV in West Africa, the worst of more than 30 in the past 40 years, comprised more than 28,000 cases and over 11,000 deaths (11). In [...]

Hepatitis A virus (HAV) remains enigmatic, despite 1.4 million cases worldwide annually (1). It differs radically from other picornaviruses, existing in an enveloped form (2) and being unusually stable, both genetically and physically (3), but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site (4), while structure-based predictions (5) suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 'domain swap' characteristic of insect picorna-like viruses (6,7), and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis (8,9)., HAV is unique among picornaviruses in targeting the liver and continues to be a source of mortality despite a successful vaccine (10). HAV isolates belong to a single serotype (11). [...]

The crystal structure of simian immunodeficiency virus (SIV) matrix antigen (MA) indicates the formation of a trimer with many biological properties of MA. SIV is similar to the human immunodeficiency virus (HIV) and their matrix antigens are identical in about half of the sequences. MA is a part of the Pr55Gag protein that is necessary for assembly of the virion shell. MA helps in the incorporation of virus envelope protein and assembly of the Pr55Gag shell.

A characterization of the structure of a major immunogenic site on foot-and-mouth disease virus (FMDV) is reported. A previous effort to characterize the crystal structure of FMDV was hampered by poor visibility of the Arg-Gly-Asp-containing loop which attaches the virus to its cellular receptor and which is also highly antigenic. The difficulty was resolved by reducing a particular disulphide bond which enabled the description of an unambiguous infective crystal structure. The correlation of this crystal structure to key biological properties of FMDV were presented and discussed.