[Frontiers in Bioscience 9, 2788-2795, September 1, 2004]
STRUCTURE-BASED DEVELOPMENT OF A NOVEL COLLAGEN INHIBITOR FOR MMP-1: RE-DESIGNING THE FUNCTIONS OF A MATRIX PROTEIN
James M Chen 1 and Li-An Yeh 2
1Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, 2 Harvard Center for Neurodegeneration and Repair, 65 Landsdowne Street, Cambridge, MA 02139
TABLE OF CONTENTS
Collagenases are a highly specific class of enzymes (1). In their native states, collagenases cleave only native triple helical collagen molecules at a single peptide bond between Gly775-Leu776 for Type I collagen and Gly775-Ile776 for Type II collagen (1, 2, 3). The linear sequence of collagen is about 1050 amino acids in length, where three linear peptide sequences are required to form a triple helical collagen molecule. At present, there exist no crystallographic structures of collagenase bound to native triple helical collagen; nor has it been shown that collagenase recognizes the triple helical conformation of collagen. In our study, we have used an inhibitor design structure-activity based approach to show that collagenase recognizes and cleaves triple helical collagen conformations in preference to non-triple helical collagen conformations (4).