Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun, Di; Chen, Shun; Cheng, Anchun; Wang, Mingshu

Since the 1990s, crystal structures have been determined for the 3C pro s of human rhinovirus (HRV), poliovirus (PV), hepatitis A virus (HAV), foot-and-mouth disease virus (FMDV) and enterovirus 71 (EV71) [10] [11] [12] [13] . These studies have revealed two equivalent β-barrel domains in 3C pro located approximately 90˝from each other and composed of six antiparallel strands. Moreover, an extended shallow groove for substrate binding is located between the two domains [14] . A flexible surface loop, called the β-ribbon, has been observed in several picornaviral 3C pro s, including those of HRV (12 residues), PV (12 residues), and HAV (21 residues) [14, 15] . The 13-residue β-ribbon of FMDV was considered in previous studies to be disordered but was subsequently demonstrated to be flexible [16] . The β-ribbon folds over the peptide-binding groove of the enzyme and accommodates a portion of the N-terminal peptide substrate. Thus, the β-ribbon plays a crucial role in substrate recognition. According to studies of EV71 3C pro , the β-ribbon is thought to alternate between an open conformation and a closed conformation with the aid of hinge residues (Gly123 and His133) [17] . Before binding a substrate, the β-ribbon adopts an open conformation to increase substrate accessibility by exposing more substrate binding clefts; once bound, the interaction between the β-ribbon and N-terminal end of the substrate stabilizes the closed conformation to form an enzyme-substrate complex.