X-RAY STRUCTURE OF A HYDROXAMATE INHIBITOR COMPLEX OF STROMELYSIN CATALYTIC DOMAIN AND ITS COMPARISON WITH MEMBERS OF THE ZINC METALLOPROTEINASE SUPERFAMILY

Background: Stromelysin belongs to a family of zinc-dependent endopept idases referred to as matrix metalloproteinases (MMPs, matrixins) beca use of their capacity for selective degradation of various components of the extracellular matrix. Matrixins play key roles in diseases as d iverse as arthritis and cancer and hence are important targets for the rapeutic intervention. Results: The crystal structure of the stromelys in catalytic domain (SCD) with bound hydroxamate inhibitor, solved by multiple isomorphous replacement, shows a deep S-1' specificity pocket which explains differences in inhibitor binding between the collagena ses and stromelysin. The binding of calcium ions by loops at the two e nds of a beta-strand which marks the boundary of the active site provi des a structural rationale for the importance of these cations for sta bility and catalytic activity, Major differences between the matrixins are clustered in two regions forming the entrance to the active site and hence may be determinants of substrate selectivity. Conclusions: S tructural comparisons of SCD with representative members of the metall oproteinase superfamily clearly highlight the conservation of key seco ndary structural elements, in spite of major variations in the sequenc es including insertions and deletions of functional domains, However, the three-dimensional structure of SCD, which is generally closely rel ated to the collagenases, shows significant differences not only in th e peripheral regions but also in the specificity pockets; these latter differences should facilitate the rational design of specific inhibit ors.