SOLUTION STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN STROMELYSIN-1 COMPLEXED TO A POTENT, NONPEPTIDIC INHIBITOR

The full three-dimensional structure of the catalytic domain of human stromelysin-1 (SCD) complexed to a novel and potent, nonpeptidic inhib itor has been determined by nuclear magnetic resonance spectroscopy (N MR). To accurately mimic assay conditions, the structure was obtained in Tris buffer at pH 6.8 and without the presence of organic solvent. The results showed that the major site of enzyme-inhibitor interaction occurs in the S1' pocket whereas portions of the inhibitor that occup y the shallow S2' and S1 pockets remained primarily solvent exposed. B ecause this relatively small inhibitor could not deeply penetrate stro melysin's long narrow hydrophobic S1' pocket, the enzyme was found to adopt a dramatic fold in the loop region spanning residues 221-231, al lowing occupation of the solvent-accessible S1' channel by the enzyme itself. This remarkable conformational fold at the enzyme binding site resulted in constriction of the S1' loop region about the inhibitor. Examination of the tertiary structure of the stromelysin-inhibitor com plex revealed few hydrogen-bonding or hydrophobic interactions between the inhibitor and enzyme that-can contribute to overall binding energ y; hence the resultant compact structure may in part account for the r elatively high potency exhibited by this inhibitor.