[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

1 Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, 2 Harvard Center for Neurodegeneration and Repair, 65 Landsdowne Street, Cambridge, MA 02139

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
4. Results and discussion
4.1. Collagenase recognizes the collagen triple helix
4.2. The triple helix is required for catalysis
4.3. The three helical strands must be cross-linked for short helical sequences
4.4. Overview of the implications of the modeling studies
5. Conclusion
5.1. Clinical implications of the modeling studies
5.2. The structure-function relationship for collagenase activity
5.3. Our studies suggest a new drug scaffold
6. Acknowledgments
7. References

1. ABSTRACT

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).