STRUCTURE OF HUMAN RHINOVIRUS 3C PROTEASE REVEALS A TRYPSIN-LIKE POLYPEPTIDE FOLD, RNA-BINDING SITE, AND MEANS FOR CLEAVING PRECURSOR POLYPROTEIN

The structure of human rhinovirus-14 3C protease (3C(pro)) has been determined at 2.3 Angstrom resolution and refined to an R factor of 0.22. This cysteine protease folds into two topologically equivalent six-stranded beta barrels and in this sense is similar to trypsin-like serine proteases. However, there are differences in the lengths and positioning of individual beta strands as well as in loops connecting elements of secondary structure. The catalytic residues Cys-146, His-40, and Glu-71 are positioned as in serine proteases, but the oxyanion hole is moved 1-1.2 Angstrom away. Residues that bind to the 5' noncoding region of rhinovirus genomic RNA are located on the opposite side of the molecule from the active site. Interactions between individual 3C(pro) molecules in the crystal lattice suggest a model for intermolecular proteolytic cleavage of the 3CD polyprotein.