2 ANGSTROM X-RAY STRUCTURE OF ADAMALYSIN-II COMPLEXED WITH A PEPTIDE PHOSPHONATE INHIBITOR ADOPTING A RETRO-BINDING MODE

The search of reprolysin inhibitors offers the possibility of interven tion against both matrixins and ADAMs. Here we report the crystal stru cture of the complex between adamalysin II, a member of the reprolysin family, and a phosphonate inhibitor modeled on an endogenous venom tr ipeptide, The inhibitor occupies the primed region of the cleavage sit e adopting a retro-binding mode, The phosphonate group ligates the zin c ion in an asymmetric bidentate mode and the adjacent Trp indole syst em partly fills the primary specificity subsite S-1'. An adamalysin-ba sed model of tumor necrosis factor-alpha-converting enzyme (TACE) reve als a smaller S-1' pocket for this enzyme. (C) 1997 Federation of Euro pean Biochemical Societies.