MATRILYSIN-INHIBITOR COMPLEXES - COMMON THEMES AMONG METALLOPROTEASES

Matrix metalloproteases are a family of enzymes that play critical rol es in the physiological and pathological degradation of the extracellu lar matrix. These enzymes may be important therapeutic targets for the treatment of various diseases where tissue degradation is part of the pathology, such as cancer and arthritis. Matrilysin is the smallest m ember of this family of enzymes, all of which require zinc for catalyt ic activity. The first X-ray crystal structures of human matrilysin ar e presented. inhibitors of metalloproteases are often characterized by the chemical group that interacts with the active site zinc of the pr otein. The structures of matrilysin complexed with hydroxamate (maximu m resolution 1.9 Angstrom), carboxylate (maximum resolution 2.4 Angstr om), and sulfodiimine (maximum resolution 2.3 Angstrom) inhibitors are presented here and provide detailed information about how each functi onal group interacts with the catalytic zinc. Only the zinc-coordinati on group is variable in this series of inhibitors. Examination of thes e inhibitor-matrilysin complexes emphasizes the dominant role the zinc -coordinating group plays in determining the relative potencies of the inhibitors. The structures of these matrilysin-inhibitor complexes al so provide a basis for comparing the catalytic mechanism of MMPs and o ther metalloproteins,