PICORNAVIRAL 3C CYSTEINE PROTEINASES HAVE A FOLD SIMILAR TO CHYMOTRYPSIN-LIKE SERINE PROTEINASES

THE picornavirus family includes several pathogens such as poliovirus, rhinovirus (the major cause of the common cold), hepatitis A virus an d the foot-and-mouth disease virus. Picornaviral proteins are expresse d by direct translation of the genomic RNA into a single, large polypr otein precursor(1,2). Proteolysis of the viral polyprotein into the ma ture proteins is assured by the viral 3C enzymes, which are cysteine p roteinases(3-6). Here we report the Xray crystal structure at 2.3 Angs trom resolution of the 3C proteinase from hepatitis A virus (HAV-3C). The overall architecture of HAV-3C reveals a fold resembling that of t he chymotrypsin family of serine proteinases, which is consistent with earlier predictions(7,8). Catalytic residues include Cys 172 as nucle ophile and His 44 as general base. The 3C cleavage specificity for glu tamine residues is defined primarily by His 191. The overall structure suggests that an intermolecular (trans) cleavage releases 3C and that there is an active proteinase in the polyprotein.