STROMELYSIN-1 - 3-DIMENSIONAL STRUCTURE OF THE INHIBITED CATALYTIC DOMAIN AND OF THE C-TRUNCATED PROENZYME

The proteolytic enzyme stromelysin-l is a member of the family of matr ix metalloproteinases and is believed to play a role in pathological c onditions such as arthritis and tumor invasion. Stromelysin-1 is synth esized as a proenzyme that is activated by removal of an N-terminal pr odomain. The active enzyme contains a catalytic domain and a C-termina l hemopexin domain believed to participate in macromolecular substrate recognition. We have determined the three-dimensional structures of b oth a C-truncated form of the proenzyme and an inhibited complex of th e catalytic domain by X-ray diffraction analysis. The catalytic core i s very similar in the two forms and is similar to the homologous domai n in fibroblast and neutrophil collagenases, as well as to the stromel ysin structure determined by NMR. The prodomain is a separate folding unit containing three alpha-helices and an extended peptide that lies in the active site of the enzyme. Surprisingly, the amino-to-carboxyl direction of this peptide chain is opposite to that adopted by the inh ibitor and by previously reported inhibitors of collagenase. Compariso n of the active site of stromelysin with that of thermolysin reveals t hat most of the residues proposed to pray significant roles in the enz ymatic mechanism of thermolysin have equivalents in stromelysin, but t hat three residues implicated in the catalytic mechanism of thermolysi n are not represented in stromelysin.