Viral Proteases: Evolution of Diverse Structural Motifs to Optimize Function

The various viral proteases discussed here serve as examples of the diversity in the structural motifs so far discovered (Figure 1Figure 1). These structures encompass the fundamental aspects of a protease: a substrate binding cleft, a reaction center, and a mechanism for transition state stabilization to permit catalysis (Perona and Craik 1995xPerona, J.P and Craik, C.S. Prot. Sci. 1995; 4: 337–360Crossref | PubMedSee all ReferencesPerona and Craik 1995). The many variations on the protein folds and catalytic residues displayed by these enzymes (Table 1Table 1) are not surprising when their origins are examined. Assuming that evolution will explore the limits of the allowed protein structures that are compatible with retention or acquisition of function, then viruses are particularly capable of achieving this task. Their replication occurs on a scale much accelerated when compared to eukaryotes, especially RNA viruses that lack proofreading mechanisms and can thus introduce many mutations. Selection for tolerable mutations is built-in since only viable viruses survive, expediting the search for structures that achieve the two major constraints placed on enzymes: preservation of catalytic competence and structural stability.Viral proteases are optimized to regulate and coordinate viral replication and assembly. Unlike digestive enzymes, they are highly selective catalysts performing limited proteolysis. The evolved protease sequence may not be the most catalytically robust enzyme, but one capable of performing proteolysis as well as other roles in viral replication. The ability of a viral protease to associate with the viral genome, become a core protein, or accommodate a cofactor may result in structural compromises leading to less efficient enzymes. But colocalization of enzyme and substrate within a virion may serve to compensate for reduced activity and may also impede random hydrolysis of host proteins. Perhaps these unique folds and structural complexities (Figure 1Figure 1) may lead to novel antiviral designs that extend beyond active site–directed, small molecules, selectively inhibiting these enzymes while not affecting host functions (Babe et al. 1995xBabe, L.M, Rose, J, and Craik, C.S. Proc. Natl. Acad. Sci. USA. 1995; 92: 10069–10073Crossref | PubMed | Scopus (48)See all ReferencesBabe et al. 1995). The uniqueness of viral proteases could become the ultimate “Achilles' heel” of the virus, as seen recently with effective HIV PR antiviral therapies.