STRUCTURAL BASIS FOR SPECIFICITY OF PAPAIN-LIKE CYSTEINE PROTEASE PROREGIONS TOWARD THEIR COGNATE ENZYMES

Synthetic peptides corresponding to the proregions of papain-like cyst eine proteases have been shown to be good and selective inhibitors of their parental enzymes. The molecular basis for their selectivity, qui te remarkable in some cases, is not fully understood. The recent deter mination of the crystal structures of three distinct papain-like cyste ine protease zymogens allows detailed structural comparisons to be mad e. The reasons for the specificity shown by each proregion toward its cognate enzyme are explained in terms of the three-dimensional structu re of the proregion and the interface between the mature enzyme and th e proregion. These comparisons reveal that insertion and substitution of amino acids within the proregion cause major rearrangement of sidec hains on the enzyme/proregion interface, allowing detailed surface and charge recognition. (C) 1998 Wiley-Liss, Inc.