Batimastat, a Potent Matrix Metalloproteinase Inhibitor, Exhibits an Unexpected Mode of Binding

*Biographics Laboratory, Dept. of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843;

**Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892.

Communicated to Proc. Natl. Acad. Sci. USA by Sir Derek H. R. Barton, FRS

Matrix metalloproteinase enzymes have been implicated in degradative processes like tumor cell invasion, metastasis, and arthritis. Specific metalloproteinase inhibitors have been used to block tumor cell proliferation. We have examined the interaction of batimastat (BB-94) with a metalloproteinase [atrolysin C (Ht-d), EC 3.4.24.42] active site at 2.0 A resolution (R=16.8%). The title structure exhibits an unexpected binding geometry, with the thiophene ring deeply inserted into the primary specificity site. This unprecedented binding geometry dramatizes the significance of the cavernous primary specificity site, pointing the way for the design of a new generation of potential antitumor drugs.

"Batimastat, A Potent Matrix Metalloproteinase Inhibitor with an Unexpected Mode of Binding", I. Botos, D. Zhang, L Scapozza, L.A. Liotta & E.F.Meyer, (1996) Proc.Natl.Acad.Sci.USA, 93:2749-2754.

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