Foot-and-mouth disease virus 3C protease: recent structural and functional insights into an antiviral target

Abstract

The 3C protease from foot-and-mouth disease virus (FMDV 3C(pro)) is critical for viral pathogenesis, having vital roles in both the processing of the polyprotein precursor and RNA replication. Although recent structural and functional studies have revealed new insights into the mechanism and function of the enzyme, key questions remain that must be addressed before the potential of FMDV 3C(pro) as an antiviral drug target can be realised.

Fig. 1

Cleavage of the FMDV polyprotein. 3C^pro cleavage sites are indicated by black arrows.

Fig. 2

Structure of FMDV 3C^pro. (a) Overall structure of the protease, coloured by secondary structure; the strands of the front and back β-sheets of the two β-barrels are coloured green and blue respectively; helices are coloured pink and the β-ribbon that folds over the active site is coloured orange. Ser 142 in the β-ribbon is indicated; this was mutated from Cys to make the protein soluble for crystallisation, a substitution that reduces the enzyme activity (Sweeney et al., 2006). (b) Close-up view of the active site showing the residues of the catalytic triad. Note that the catalytic nucleophile (Cys 163) was mutated to Ala in the crystal structure (Sweeney et al., 2006) but has been modelled here as the original sidechain. The interaction between Asp 84 and His 46 is essentially identical to that observed in serine proteases, suggesting that it has a conserved function in catalysis. The oxyanion hole, another key feature of serine proteases that is also conserved in FMDV 3C^pro, is formed by the amide groups of Gly 161 and Cys 163. (c) Sequence logos of the polyprotein junctions cleaved by FMDV 3C^pro. Sequences from over 100 strains of FMDV (Carrillo et al., 2005) were aligned, split into two groups (P1-Gln and P1-Glu) and used to generate logos using Weblogo (http://weblogo.berkeley.edu/). (d) Structure of the dorsal surface of FMDV 3C^pro, opposite to the active site showing residues that contribute to RNA binding and VPg uridylylation (Nayak et al., 2006). The view is rotated 180° about a vertical axis with respect to the orientation shown in panel (a).