Crystal Structures Of Stromelysin Catalytic Domain (Scd) With Non-Peptide Inhibitors. A. G. Pavlovsky, D. F. Ortwine, Q. Z. Ye, L. L. Johnson, C. F. Purchase, A. D. White, C. Humblet, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105

Stromelysin (MMP3) is a member of the matrix metalloproteinase family of enzymes that include collagenases and gelatinases. This enzyme family has been shown to play a key role in physiological development and pathological tissue degradation, and when overexpressed, are believed to be involved in the etiology of diseases such as arthritis and cancer.

As part of structure-based drug design program in this area, four non-peptide/SCD inhibitor complexes have been co-crystallized and studied by X-ray crystallography. Their structures have been solved by molecular replacement methods using AMoRe¹ and refined by XPLOR² using high resolution data. The tight binding observed for these inhibitors is supported by key interactions between the inhibitor and the active site of the protein. The most important, as seen from the structure analyses, are hydrophobic interactions in the P1' pocket as well as ligation to the catalytic Zn. The crystallization conditions employed, details of the structure refinement, and the nature of the observed interactions between inhibitor and protein will be described.

¹J.Navaza (1994), Acta Cryst. A50, 157-163.

²A.T.Brünger XPLOR, Version 3.0 (Yale Univ., New Haven, 1992).